CD44 acts as a coreceptor for cell-specific enhancement of signaling and regulatory T cell induction by TGM1, a parasite TGF-ß mimic.

Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus, down-modulates the host immune system through release of an immunosuppressive TGF-ß mimic, TGM1, which is a divergent member of the CCP (Sushi) protein family. TGM1 comprises 5 domains, of which domains 1-3 (D1/2/3) bind mammalian TGF-ß receptors, acting on T cells to induce Foxp3+ regulatory T cells; however, the roles of domains 4 and 5 (D4/5) remain unknown. We noted that truncated TGM1, lacking D4/5, showed reduced potency. Combination of D1/2/3 and D4/5 as separate proteins did not alter potency, suggesting that a physical linkage is required and that these domains do not deliver an independent signal. Coprecipitation from cells treated with biotinylated D4/5, followed by mass spectrometry, identified the cell surface protein CD44 as a coreceptor for TGM1. Both full-length and D4/5 bound strongly to a range of primary cells and cell lines, to a greater degree than D1/2/3 alone, although some cell lines did not respond to TGM1. Ectopic expression of CD44 in nonresponding cells conferred responsiveness, while genetic depletion of CD44 abolished enhancement by D4/5 and ablated the ability of full-length TGM1 to bind to cell surfaces. Moreover, CD44-deficient T cells showed attenuated induction of Foxp3 by full-length TGM1, to levels similar to those induced by D1/2/3. Hence, a parasite protein known to bind two host cytokine receptor subunits has evolved a third receptor specificity, which serves to raise the avidity and cell type-specific potency of TGF-ß signaling in mammalian cells.

Unlocking hidden potential: advancements, approaches, and obstacles in repurposing drugs for cancer therapy.

High rates of failure, exorbitant costs, and the sluggish pace of new drug discovery and development have led to a growing interest in repurposing "old" drugs to treat both common and rare diseases, particularly cancer. Cancer, a complex and heterogeneous disease, often necessitates a combination of different treatment modalities to achieve optimal outcomes. The intrinsic polygenicity of cancer, intricate biological signalling networks, and feedback loops make the inhibition of a single target frequently insufficient for achieving the desired therapeutic impact. As a result, addressing these complex or "smart" malignancies demands equally sophisticated treatment strategies. Combinatory treatments that target the multifaceted oncogenic signalling network hold immense promise. Repurposed drugs offer a potential solution to this challenge, harnessing known compounds for new indications. By avoiding the prohibitive costs and long development timelines associated with novel cancer drugs, this approach holds the potential to usher in more effective, efficient, and cost-effective cancer treatments. The pursuit of combinatory therapies through drug repurposing may hold the key to achieving superior outcomes for cancer patients. However, drug repurposing faces significant commercial, technological and regulatory challenges that need to be addressed. This review explores the diverse approaches employed in drug repurposing, delves into the challenges faced by the drug repurposing community, and presents innovative solutions to overcome these obstacles. By emphasising the significance of combinatory treatments within the context of drug repurposing, we aim to unlock the full potential of this approach for enhancing cancer therapy. The positive aspects of drug repurposing in oncology are underscored here; encompassing personalized treatment, accelerated development, market opportunities for shelved drugs, cancer prevention, expanded patient reach, improved patient access, multi-partner collaborations, increased likelihood of approval, reduced costs, and enhanced combination therapy.

The tumour microenvironment, treatment resistance and recurrence in glioblastoma.

The adaptability of glioblastoma (GBM) cells, encouraged by complex interactions with the tumour microenvironment (TME), currently renders GBM an incurable cancer. Despite intensive research, with many clinical trials, GBM patients rely on standard treatments including surgery followed by radiation and chemotherapy, which have been observed to induce a more aggressive phenotype in recurrent tumours. This failure to improve treatments is undoubtedly a result of insufficient models which fail to incorporate components of the human brain TME. Research has increasingly uncovered mechanisms of tumour-TME interactions that correlate to worsened patient prognoses, including tumour-associated astrocyte mitochondrial transfer, neuronal circuit remodelling and immunosuppression. This tumour hijacked TME is highly implicated in driving therapy resistance, with further alterations within the TME and tumour resulting from therapy exposure inducing increased tumour growth and invasion. Recent developments improving organoid models, including aspects of the TME, are paving an exciting future for the research and drug development for GBM, with the hopes of improving patient survival growing closer. This review focuses on GBMs interactions with the TME and their effect on tumour pathology and treatment efficiency, with a look at challenges GBM models face in sufficiently recapitulating this complex and highly adaptive cancer.

Recent advances in understanding the molecular basis of infantile haemangioma development.

Infantile haemangioma (IH) - the most common vascular tumour of infancy - is comprised of diverse cell types, including endothelial cells, pericytes, fibroblasts and immune cells. IH is characterized by rapid proliferation followed by slow involution over 1-10 years. Most lesions regress spontaneously, but up to 10% can be disfiguring, with complications that require further medical treatment. Recent research has revealed the biological characteristics of IH, highlighting the involvement of angiogenesis and vasculogenesis during tumour formation. Gene expression profiling has provided vital insights into the underlying biological processes, with some of the key IH-related pathways identified, including vascular endothelial growth factor, the renin-angiotensin-aldosterone system, hypoxia-inducible factor 1α, Notch, platelet-derived growth factor, phosphoinositide 3-kinase/Akt/mammalian target of rapamycin, Janus kinase/signal transducers and activators of transcription, fibroblast growth factor, peroxisome proliferator-activated receptor-γ and insulin-like growth factor. Further evidence suggests extracellular matrix factors and hormone receptors regulate IH progression. In this review, we explore the molecular mechanisms involved in the proliferating, plateau and involuting phases of IH, identifying differentially expressed genes, targeted proteins and key signalling pathways. This knowledge will increase the broader understanding of vascular development, tissue remodelling and angiogenesis.

Infantile haemangioma is a common vascular tumour (or birthmark) that affects babies. Less is known about the pathways involved in their development and progression. We look at the key proteins involved in the development of these tumours. These proteins help new blood vessels grow (called 'angiogenesis') when a tumour is just starting to appear. The area around the tumour becomes inflamed, and the immune system releases molecules called 'cytokines' that help new blood vessels grow and to increase the number of cells (called 'proliferation'). Within a year, the tumours shrink and are gradually replaced by fatty tissue (called 'spontaneous involution'). This phase is influenced by other proteins called 'IGF' and 'PPAR-γ', which encourage cell death and tissue remodelling. Hormone receptors and the area outside cells called the 'extracellular matrix' could be the key to understanding this change. Even though many protein signalling pathways are involved in the two phases, we still do not know exactly how the switch between them happens. This review explains the molecular mechanisms behind infantile haemangiomas, focusing on how the protein signalling pathways work together. Our research offers valuable insights for both researchers and clinicians in this field.

Resistance Training-Induced Acute Hypoalgesia in Women With Persistent Pain After Breast Cancer Treatment.

ABSTRACT: Fogh Rasmussen, GH, Madeleine, P, Arroyo-Morales, M, Voigt, M, and Kristiansen, M. Resistance training-induced acute hypoalgesia in women with persistent pain after breast cancer treatment. J Strength Cond Res 37(3): e16-e24, 2023-The aim of this study was to determine whether a single bout of resistance training (RT) produces acute exercise-induced hypoalgesia (EIH) in breast cancer survivors (BCS) suffering from persistent pain ≥1.5 years after treatment. Twenty individuals with self-reported pain ≥3 on a 0-10 Numerical Rating Scale after treatment for breast cancer completed 3 experimental sessions, (a) familiarization; (b) 1 repetition maximum (1RM) normalization, and (c) training, consisting of 3 sets of 10 repetitions at 60% of 1 repetition maximum. Pressure pain thresholds (PPTs) were measured before and after training for the dorsal and ventral shoulder regions of the affected side. Movement-evoked pain (MEP) and rating of perceived exertion (RPE) were collected immediately after each set. A p -value less than 0.05 was considered statistically significant. The results demonstrated a significant increase in PPTs of the ventral shoulder region after a single bout of RT ( p ≤ 0.05), indicating a localized analgesic response for this area. By contrast, no change was detected in PPTs on the dorsal shoulder region. No significant differences were found in MEP between sessions despite a significant increase in load and RPE during 1RM assessment ( p ≤ 0.05), indicating that MEP was not affected by increase in absolute and relative intensity. In conclusion, a single bout of submaximal RT reduced PPTs for the ventral shoulder region of BCS with persistent pain after treatment and was well tolerated. Hence, RT may be a useful therapeutic tool for managing persistent pain after breast cancer treatment in clinical practice.

The parasite cytokine mimic Hp-TGM potently replicates the regulatory effects of TGF-ß on murine CD4+ T cells.

Transforming growth factor-beta (TGF-ß) family proteins mediate many vital biological functions in growth, development and regulation of the immune system. TGF-ß itself controls immune homeostasis and inflammation, including conversion of naïve CD4+ T cells into Foxp3+ regulatory T cells (Tregs) in the presence of interleukin-2 and T-cell receptor ligands. The helminth parasite Heligmosomoides polygyrus exploits this pathway through a structurally novel TGF-ß mimic (Hp-TGM), which binds to mammalian TGF-ß receptors and induces Tregs. Here, we performed detailed comparisons of Hp-TGM with mammalian TGF-ß. Compared with TGF-ß, Hp-TGM induced greater numbers of Foxp3+ Tregs (iTregs), with more intense Foxp3 expression. Both ligands upregulated Treg functional markers CD73, CD103 and programmed death-ligand 1, but Hp-TGM induced significantly higher CD39 expression than did TGF-ß. Interestingly, in contrast to canonical TGF-ß signaling through Smad2/3, Hp-TGM stimulation was slower and more sustained. Gene expression profiles induced by TGF-ß and Hp-TGM were remarkably similar, and both types of iTregs suppressed T-cell responses in vitro and experimental autoimmune encephalomyelitis-driven inflammation in vivo. In vitro, both types of iTregs were equally stable under inflammatory conditions, but Hp-TGM-induced iTregs were more stable in vivo during dextran sodium sulfate-induced colitis, with greater retention of Foxp3 expression and lower conversion to a ROR-γt+ phenotype. Altogether, results from this study suggest that the parasite cytokine mimic, Hp-TGM, may deliver a qualitatively different signal to CD4+ T cells with downstream consequences for the long-term stability of iTregs. These data highlight the potential of Hp-TGM as a new modulator of T-cell responses in vitro and in vivo.

Regulatory T-cells in helminth infection: induction, function and therapeutic potential.

Helminth parasites infect an alarmingly large proportion of the world's population, primarily within tropical regions, and their ability to down-modulate host immunity is key to their persistence. Helminths have developed multiple mechanisms that induce a state of hyporesponsiveness or immune suppression within the host; of particular interest are mechanisms that drive the induction of regulatory T-cells (Tregs). Helminths actively induce Tregs either directly by secreting factors, such as the TGF-ß mimic Hp-TGM, or indirectly by interacting with bystander cell types such as dendritic cells and macrophages that then induce Tregs. Expansion of Tregs not only enhances parasite survival but, in cases such as filarial infection, Tregs also play a role in preventing parasite-associated pathologies. Furthermore, Tregs generated during helminth infection have been associated with suppression of bystander immunopathologies in a range of inflammatory conditions such as allergy and autoimmune disease. In this review, we discuss evidence from natural and experimental infections that point to the pathways and molecules involved in helminth Treg induction, and postulate how parasite-derived molecules and/or Tregs might be applied as anti-inflammatory therapies in the future.

Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury.

The liver contains diploid and polyploid hepatocytes (tetraploid, octaploid, etc.), with polyploids comprising ≥90% of the hepatocyte population in adult mice. Polyploid hepatocytes form multipolar spindles in mitosis, which lead to chromosome gains/losses and random aneuploidy. The effect of aneuploidy on liver function is unclear, and the degree of liver aneuploidy is debated, with reports showing aneuploidy affects 5% to 60% of hepatocytes. To study relationships among liver polyploidy, aneuploidy, and adaptation, mice lacking E2f7 and E2f8 in the liver (LKO), which have a polyploidization defect, were used. Polyploids were reduced fourfold in LKO livers, and LKO hepatocytes remained predominantly diploid after extensive proliferation. Moreover, nearly all LKO hepatocytes were euploid compared with control hepatocytes, suggesting polyploid hepatocytes are required for production of aneuploid progeny. To determine whether reduced polyploidy impairs adaptation, LKO mice were bred onto a tyrosinemia background, a disease model whereby the liver can develop disease-resistant, regenerative nodules. Although tyrosinemic LKO mice were more susceptible to morbidities and death associated with tyrosinemia-induced liver failure, they developed regenerating nodules similar to control mice. Analyses revealed that nodules in the tyrosinemic livers were generated by aneuploidy and inactivating mutations. In summary, we identified new roles for polyploid hepatocytes and demonstrated that they are required for the formation of aneuploid progeny and can facilitate adaptation to chronic liver disease.

The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice.

The liver contains a mixture of hepatocytes with diploid or polyploid (tetraploid, octaploid, etc.) nuclear content. Polyploid hepatocytes are commonly found in adult mammals, representing ~90% of the entire hepatic pool in rodents. The cellular and molecular mechanisms that regulate polyploidization have been well characterized; however, it is unclear whether diploid and polyploid hepatocytes function similarly in multiple contexts. Answering this question has been challenging because proliferating hepatocytes can increase or decrease ploidy, and animal models with healthy diploid-only livers have not been available. Mice lacking E2f7 and E2f8 in the liver (liver-specific E2f7/E2f8 knockout; LKO) were recently reported to have a polyploidization defect, but were otherwise healthy. Herein, livers from LKO mice were rigorously characterized, demonstrating a 20-fold increase in diploid hepatocytes and maintenance of the diploid state even after extensive proliferation. Livers from LKO mice maintained normal function, but became highly tumorigenic when challenged with tumor-promoting stimuli, suggesting that tumors in LKO mice were driven, at least in part, by diploid hepatocytes capable of rapid proliferation. Indeed, hepatocytes from LKO mice proliferate faster and out-compete control hepatocytes, especially in competitive repopulation studies. In addition, diploid or polyploid hepatocytes from wild-type (WT) mice were examined to eliminate potentially confounding effects associated with E2f7/E2f8 deficiency. WT diploid cells also showed a proliferative advantage, entering and progressing through the cell cycle faster than polyploid cells, both in vitro and during liver regeneration (LR). Diploid and polyploid hepatocytes responded similarly to hepatic mitogens, indicating that proliferation kinetics are unrelated to differential response to growth stimuli. Conclusion: Diploid hepatocytes proliferate faster than polyploids, suggesting that the polyploid state functions as a growth suppressor to restrict proliferation by the majority of hepatocytes.

Outcomes of sinonasal mucosal melanomas with endoscopic and open resection: a retrospective cohort study.

PURPOSE: To compare the outcomes of Sinonasal Mucosal Melanomas (SNMM) treated with endoscopic and open resection. METHODS: A retrospective case review of 20 patients with SNMM treated surgically at UCSF. Kaplan-Meier analyses were calculated to determine outcome differences in endoscopic vs. open resections. RESULTS: From 2005 to 2014, 20 cases of SNMM were confirmed and treated at UCSF. All cases underwent surgical resection, with 10 cases by open resection and 10 cases by endoscopic resection. Using Kaplan-Meier analyses, the open resection group had a 1-year survival of 30% whereas endoscopic resection group was 80% (p = 0.032). Endoscopic resection showed improved survival at all time points after surgery compared to open resection. CONCLUSION: SNMM is a rare and aggressive tumor that is associated with low survival rates. In this small case series, endoscopic resection had improved survival outcomes compared to open resection.

Contemporary Management of Parapharyngeal Tumors.

PURPOSE OF REVIEW: Management of parapharyngeal tumors is challenging due to the complex anatomic nature of the space and the wide range of pathologies encountered. This article will review the anatomy, common pathologies, and management of parapharyngeal masses. Surgical strategies are also reviewed. RECENT FINDINGS: Masses of the parapharyngeal space are most commonly benign (80%). More recent longitudinal studies have shown that observation and non-surgical therapy are indicated in many cases. When surgery is indicated, innovative endoscopic and robotic-assisted techniques allow for improved visualization and complete tumor removal while avoiding significant blood loss, tumor spillage, and injury to surrounding nerves and vessels. Management of parapharyngeal masses should consider morbidity of surgical resection versus the natural course of the disease. Surgical strategy is determined by location, size, and pathology. Adequate access is needed surgically to ensure complete resection and avoid tumor rupture.

Can Early Dental Extractions Reduce Delays in Postoperative Radiation for Patients With Advanced Oral Cavity Carcinoma?

PURPOSE: This study sought to evaluate the effect of early extractions on the timing of postoperative radiation (PORT) for patients with advanced oral cavity squamous cell carcinoma. MATERIALS AND METHODS: All patients with oral cavity squamous cell carcinoma who required resection, free flap reconstruction, and dental extractions in a 10-year period were retrospectively reviewed. The study included patients who preoperatively had advanced disease that indicated the need for adjuvant radiation as defined by an advanced clinical T category (T3 or T4a) or clinical N category (N2a or above). Multivariate logistic regression models were created to estimate the risk factors for initiation of PORT greater than 6 weeks after surgery. RESULTS: Thirty-four patients were included. Thirteen patients underwent early extractions (before or at the time of surgery). Twenty-one patients underwent extractions after surgery. Extractions included all teeth with periodontal disease within the expected field of radiation. Most patients underwent full-mouth extractions (91.1%). PORT was initiated at greater than 6 weeks in 30.8% of patients in the early cohort, whereas 72.4% of patients in the late group experienced a delay (P = .02). Early extractions were significantly associated with a decreased risk of PORT delay. No increase in operating room time occurred for patients who underwent same-day extractions. CONCLUSIONS: Early involvement of the dental oncology department and oral-maxillofacial surgeons can aid in the timely delivery of care for patients with advanced oral cavity cancer.

Eccentric exercise induces spatial changes in the mechanomyographic activity of the upper trapezius muscle.

In this study, we hypothesized that the recordings of multichannel mechanomyography (MMG) of the upper trapezius muscle would reveal spatially dependent manifestations in the presence of delayed onset muscle soreness occurring 24 hours after eccentric exercise (ECC). Sixteen participants performed high-intensity eccentric exercises (5 sets of 10 eccentric contractions at 100% of max elevation force) targeting the upper trapezius on their dominant side. Twelve accelerometers were attached to record MMG activity during submaximal exercise consisting of static and dynamic arm flexion and abduction. Measurements were taken before and 24 hours after ECC. Average rectified value (ARV), percentage of determinism (% DET), and recurrence (% REC) of the MMG signals were computed to estimate the level of muscular activity and the magnitude of regularity of the MMG. The ARV, % REC, and % DET maps revealed heterogeneous MMG activity of the upper trapezius 24 hours after ECC when compared with before. Increased ARV, % REC, and % DET were found 24 hours after ECC when compared with before. The study provides new key information on how a single muscle responds to ECC. Our findings suggest that multichannel MMG and nonlinear analyses may detect muscular and musculo-tendinous alterations due to ECC.

Surgeon-performed ultrasound for the assessment of parotid masses.

BACKGROUND: Studies on parotid gland ultrasound assessments performed specifically by surgeons are seldom reported. METHODS: Retrospective series of a single academic surgeon experience, analyzing 70 new parotid masses with evaluable preoperative SP-US characteristics, location measurements, and perioperative events. RESULTS: 31/70 masses were malignant. SP-US characteristics significantly associated with both malignancy and positive margins included extraparenchymal extension, irregular borders, hypervascularity, infiltration, and the lack of deep enhancement. The larger the skin-to-deep-aspect-of-tumor distance, the more likely the tumor was deep to FN. For the 39 cytologically benign tumors, neither CT nor MRI provided additional information to change management except for full delineation of parapharyngeal space extension in 2 cases. CONCLUSION: SP-US can help predict parotid mass benignity/malignancy, positive margin risk, and tumor relation to FN. SP-US may be used as the sole imaging in cytologically benign tumors unless the deep tumor extent cannot be identified.

Carrier Scattering at Alloy Nanointerfaces Enhances Power Factor in PEDOT:PSS Hybrid Thermoelectrics.

UNLABELLED: This work demonstrates the first method for controlled growth of heterostructures within hybrid organic/inorganic nanocomposite thermoelectrics. Using a facile, aqueous technique, semimetal-alloy nanointerfaces are patterned within a hybrid thermoelectric system consisting of tellurium (Te) nanowires and the conducting polymer poly(3,4-ethylenedioxythiophene):poly(styrene-sulfonate) ( PEDOT: PSS). Specifically, this method is used to grow nanoscale islands of Cu1.75Te alloy subphases within hybrid PEDOT: PSS-Te nanowires. This technique is shown to provide tunability of thermoelectric and electronic properties, providing up to 22% enhancement of the system's power factor in the low-doping regime, consistent with preferential scattering of low energy carriers. This work provides an exciting platform for rational design of multiphase nanocomposites and highlights the potential for engineering of carrier filtering within hybrid thermoelectrics via introduction of interfaces with controlled structural and energetic properties.

Inter-subject variability of muscle synergies during bench press in power lifters and untrained individuals.

The purpose of the study was to elucidate the role of expertise on muscle synergies involved in bench press. Ten expert power lifters (EXP) and nine untrained participants (UNT) completed three sets of eight repetitions at 60% of three repetition maximum in bench press. Muscle synergies were extracted from surface electromyography data of 21 bench press cycles using non-negative matrix factorization algorithm. The synergy activation coefficient represents the relative contribution of the muscle synergy to the overall muscle activity pattern, while the muscle synergy vector represents the relative weighting of each muscle within each synergy. Describing more than 90% of the variability, two muscle synergies reflected the eccentric and concentric phase. The cross-correlations (ρ(max)) for synergy activation coefficient 2 (concentric phase) were 0.83 [0.71;0.88] and 0.59 [0.49;0.77] [Median ρ(max) (25th;75th percentile)] (P = 0.001) in UNT and EXP, respectively. Median correlation coefficient (ρ) for muscle synergy vector 2 was 0.15 [-0.08;0.46] and 0.48 [0.02;0.70] (P = 0.03) in UNT and EXP, respectively. Thus, EXP showed larger inter-subject variability than UNT in the synergy activation coefficient during the concentric phase, while the muscle synergy vectors were less variable in EXP. This points at the importance of a specialized neural strategy in elite bench press performance.

A public resource facilitating clinical use of genomes.

Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentifiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project choose to forgo privacy via our institutional review board- approved "open consent" process. The contribution of public data and samples facilitates both scientific discovery and standardization of methods. We present our findings after enrollment of more than 1,800 participants, including whole-genome sequencing of 10 pilot participant genomes (the PGP-10). We introduce the Genome-Environment-Trait Evidence (GET-Evidence) system. This tool automatically processes genomes and prioritizes both published and novel variants for interpretation. In the process of reviewing the presumed healthy PGP-10 genomes, we find numerous literature references implying serious disease. Although it is sometimes impossible to rule out a late-onset effect, stringent evidence requirements can address the high rate of incidental findings. To that end we develop a peer production system for recording and organizing variant evaluations according to standard evidence guidelines, creating a public forum for reaching consensus on interpretation of clinically relevant variants. Genome analysis becomes a two-step process: using a prioritized list to record variant evaluations, then automatically sorting reviewed variants using these annotations. Genome data, health and trait information, participant samples, and variant interpretations are all shared in the public domain-we invite others to review our results using our participant samples and contribute to our interpretations. We offer our public resource and methods to further personalized medical research.

Phased whole-genome genetic risk in a family quartet using a major allele reference sequence.

Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.

Effects of two recovery procedures after a football game on sensory and biochemical markers.

AIM: The aim of this study was to investigate recovery processes on pressure pain sensitivity and blood indicators in professional football players after three different post-game training modalities: standard recovery training, no physical activity, delayed onset muscle soreness reduction training. METHODS: Eleven male football field players participated in the present study. The experiment was performed in three sessions over three weeks after three football league games. The procedure was composed of the following assessments included in each session: measurement of pain pressure threshold, creatine kinase activity and myoglobin (Mb) concentration before, 24 and 48 hours after game. RESULTS: In standard recovery training there was no full recovery in deep structure sensitivity of the frontal thigh muscles at 48 hours after game (P=0.008). In the no physical activity session, sensitivity returned to its level before game. On the contrary, in the delayed onset muscle soreness reduction training sensitivity decreased 48 hours after game (P<0.001). Creatine kinase activity decreased significantly from 24 hours to 48 hours in session with no activity and delayed onset muscle soreness reduction training (P<0.05). None of the recovery methods had an influence on Mb concentration. CONCLUSION: The present study points towards a potent effect of delayed onset muscle soreness reduction training on recovery after a football game.

Subgrouping of facilitatory or inhibitory conditioned pain modulation responses in patients with chronic knee pain. Explorative analysis from a multicentre trial.

BACKGROUND: Facilitatory and inhibitory conditioned pain modulation (CPM) responses are observed in healthy volunteers and chronic pain patients, but the clinical implications for phenotyping are unknown. This study aimed to subgroup and compare chronic knee pain patients according to their CPM responses. METHODS: This explorative, cross-sectional study included 127 patients with chronic knee pain (osteoarthritis or following total knee arthroplasty). Individual CPM responses were categorized as facilitatory (test stimuli pain intensity increased when conditioning stimuli were applied), as inhibitory (test stimuli pain intensity decreased) or as no change (defined as less than 5.3% change in pain intensity). Outcomes were clinical pain intensities, temporal summation, widespread pain, self-reported physical function, PainDETECT questionnaire and Pain Quality Assessment Scale. Data were analysed as comparisons between the inhibitory and the facilitatory groups and using multivariate linear regression models. RESULTS: Fifty-four patients had facilitatory CPM responses, 49 had inhibitory CPM responses, and 24 showed no change in CPM response. A between-group difference was observed for self-reported physical function, with the facilitatory CPM group reporting better function (54.4 vs. 46.0, p = 0.028) and the facilitatory CPM group reported more deep pain sensations (3.2 vs. 2.0, p = 0.021). The remaining outcomes showed no between-group differences. Higher clinical pain intensity and facilitated temporal summation were associated in the facilitated CPM group but not in the inhibitory CPM group. CONCLUSION: These explorative findings indicated that quantitative clinical and experimental differences exist between facilitatory or inhibitory CPM responses in a chronic knee pain patient population. Differences in patients' CPM responses should be further investigated to unravel possible clinical importance. SIGNIFICANCE: Our findings confirm that conditioned pain modulation consist of inhibitory and facilitatory responders among a patient population with chronic knee pain. This explorative study indicates that patients with either facilitatory or inhibitory conditioned pain modulation could exhibit differences in pain outcomes. Subgrouping of chronic pain patients depending on individual conditioned pain modulation responses could be considered in phenotyping patients prior to inclusion in clinical trials or used for personalizing the management regime.