Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors.

Background: Poly (ADP-Ribose) polymerase inhibitors are approved for treatment of tumors with BRCA1/2 and other homologous recombination repair (HRR) mutations. However, clinical responses are often not durable and treatment may be detrimental in advanced cancer due to excessive toxicities. Thus we are seeking alternative therapeutics to enhance PARP-directed outcomes.

Sensory alterations and immunological changes during the chronification of postsurgical pain: a study protocol for a prospective observational cohort study.

Introduction: Chronic postsurgical pain (CPSP) represents a widely underdiagnosed and often poorly treated medical problem, affecting 10-50% of all surgical patients, exhibiting neuropathic features in 35-60%. It is hypothesised that surgery-induced tissue damage and the subsequent immune response cause sensory alterations in the early postoperative period, ultimately leading to a chronic neuropathic or nociplastic pain state. The 'Sensory Changes and Immunological parameters in Postsurgical pain' study (SCIP-Pain study) was designed to test this hypothesis and identify sensory alterations and changes in the immunological response that are related to the development of CPSP with neuropathic features.

Electronic health record modification and dashboard development to improve clinical care in pediatric rheumatology.

Objective: This report describes our experience in electronic health record (EHR) note modification and creation of an external dashboard to create a local learning health system that contributes to quality improvement and patient care within our pediatric rheumatology clinic.

Methods: We applied quality improvement methodology to develop a more reliable and accurate system to identify patients with juvenile idiopathic arthritis and track important measures that aide in improving patient care and performance outcomes. From 2019 to 2021, we iteratively modified our outpatient clinic EHR note to include structured data elements to improve longitudinal monitoring.

Overcoming the Chemical Complexity Bottleneck in on-the-Fly Machine Learned Molecular Dynamics Simulations.

We develop a framework for on-the-fly machine learned force field molecular dynamics simulations based on the multipole featurization scheme that overcomes the bottleneck with the number of chemical elements. Considering bulk systems with up to 6 elements, we demonstrate that the number of density functional theory calls remains approximately independent of the number of chemical elements, in contrast to the increase in the smooth overlap of the atomic positions scheme.

In vitro T cell responses to PD-1 blockade are reduced by IFN-α but do not predict therapy response in melanoma patients.

PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro.

Experimental Data on PIRCHE and T-Cell Reactivity: HLA-DPB1-Derived Peptides Identified by PIRCHE-I Show Binding to HLA-A*02:01 in vitro and T-Cell Activation in vivo.

Introduction: Human leukocyte antigen (HLA)-DPB1 mismatches during hematopoietic stem cell transplantation (HSCT) with an unrelated donor result in an increased risk for the development of graft-versus-host disease (GvHD). The number of CD8 T-cell epitopes available for indirect allorecognition as predicted by the PIRCHE algorithm has been shown to be associated with GvHD development. As a proof of principle, PIRCHE-I predictions for HLA-DPB1 mismatches were validated in vitro and in vivo.

Multimodal analgesia practices for knee and hip arthroplasties in the Netherlands. A prospective observational study from the PAIN OUT registry.

Introduction: Different multimodal pain management strategies following total hip arthroplasty(THA) and total knee arthroplasty (TKA) surgery are used in clinical practice. The optimal pain management strategy, however, remains unclear. This study aims to evaluate the differences in perioperative multimodal pain management strategies for THA and TKA in the Netherlands, and studies the associations between patient- and therapy related factors and pain outcomes.

Preoperative frailty and chronic pain after cardiac surgery: a prospective observational study.

Background: Chronic pain after cardiac surgery, whether or not related to the operation, is common and has negative impact on health related quality of life (HRQL). Frailty is a risk factor for adverse surgical outcomes, but its relationship with chronic pain after cardiac surgery is unknown. This study aimed to address the association between frailty and chronic pain following cardiac surgery.

Identification of putative essential protein domains from high-density transposon insertion sequencing.

A first clue to gene function can be obtained by examining whether a gene is required for life in certain standard conditions, that is, whether a gene is essential. In bacteria, essential genes are usually identified by high-density transposon mutagenesis followed by sequencing of insertion sites (Tn-seq). These studies assign the term "essential" to whole genes rather than the protein domain sequences that encode the essential functions.

Signaling by the inhibitory receptor CD200R is rewired by type I interferon.

CD200 receptor 1 (CD200R) is an inhibitory immunoreceptor that suppresses Toll-like receptor (TLR)–induced cytokine production through the adaptor protein Dok2 and the GTPase activating protein (GAP) p120-RasGAP, which can be cleaved during mild cellular stress. We found that in the presence of cleaved p120-RasGAP, CD200R lost its capacity to inhibit phosphorylation of ribosomal S6 protein (rpS6), suggesting the reduced activity of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, treatment of human peripheral blood mononuclear cells (PBMC) with interferon-α (IFN-α) resulted in increased amounts of cleaved p120-RasGAP.

Direct P70S6K1 inhibition to replace dexamethasone in synergistic combination with MCL-1 inhibition in multiple myeloma.

Novel combination therapies have markedly improved the lifespan of patients with multiple myeloma (MM), but drug resistance and disease relapse remain major clinical problems. Dexamethasone and other glucocorticoids are a cornerstone of conventional and new combination therapies for MM, although their use is accompanied by serious side effects. We aimed to uncover drug combinations that act in synergy and, as such, allow reduced dosing while remaining effective.

Identification of a novel conserved signaling motif in CD200 receptor required for its inhibitory function.

The inhibitory signaling of CD200 receptor 1 (CD200R) has been attributed to its NPxY signaling motif. However, NPxY-motifs are present in multiple protein families and are mostly known to mediate protein trafficking between subcellular locations rather than signaling. Therefore, we investigated whether additional motifs specify the inhibitory function of CD200R.

Approaches to Understanding the Solution-State Organization of Spray-Dried Dispersion Feed Solutions and Its Translation to the Solid State.

It is well established that polymers adopt a range of conformations and solution-state organization in response to varying solution environments, although very little work has been done to understand how these effects might impact the physical stability and bioavailability of spray-dried amorphous dispersions (SDDs). Potentially relevant solution-state polymer-solvent/cosolute interactions include preferential solvation, hydrodynamic size (i.e.

The Relation Between Patients' Beliefs About Pain Medication, Medication Adherence, and Treatment Outcome in Chronic Pain Patients: A Prospective Study.

Objectives: Nonadherence to prescribed pain medication is common in chronic noncancer pain patients. Beliefs about pain medication have been reported to be associated with nonadherence behavior in cross-sectional studies. The aim of this study was to prospectively investigate the relationship between patients' beliefs about pain medication and their medication adherence and treatment outcome.

xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction.

About 3 million US cancer patients and 1.7 million EU cancer patients received multiple doses of radiation therapy (RT) in 2012, with treatment duration limited by normal adjacent tissue damage. Tumor-specific sensitization could allow treatment with lower radiation doses, reducing normal tissue damage.

Primary intra-articular epithelioid sarcoma of the knee: Unusual presentation of a rare entity.

We report a case of a 60-year-old female with severe and progressive pain of her right knee. Physical therapy, pain medication, and arthroscopic debridement were unsuccessful. Finally, pathological examination revealed an intra-articular epithelioid sarcoma, a rare tumor in an atypical location.

Comparative Effect of Collaborative Care, Pain Medication, and Duloxetine in the Treatment of Major Depressive Disorder and Comorbid (Sub)Chronic Pain: Results of an Exploratory Randomized, Placebo-Controlled, Multicenter Trial (CC:PAINDIP).

Objective: Evidence exists for the efficacy of collaborative care (CC) for major depressive disorder (MDD), for the efficacy of the consequent use of pain medication against pain, and for the efficacy of duloxetine against both MDD and neuropathic pain. Their relative effectiveness in comorbid MDD and pain has never been established so far. This study explores the effectiveness of CC with pain medication and duloxetine, and CC with pain medication and placebo, compared with duloxetine alone, on depressive and pain symptoms.

The effect of manual therapy and neuroplasticity education on chronic low back pain: a randomized clinical trial.

Objective: To determine if a neuroplasticity educational explanation for a manual therapy technique will produce a different outcome compared to a traditional mechanical explanation.

Methods: Sixty-two patients with chronic low back pain (CLBP) were recruited for the study. Following consent, demographic data were obtained as well as pain ratings for low back pain (LBP) and leg pain (Numeric Pain Rating Scale), disability (Oswestry Disability Index), fear-avoidance (Fear-Avoidance-Beliefs Questionnaire), forward flexion (fingertips-to-floor), and straight leg raise (SLR) (inclinometer).

The ELPAT living organ donor Psychosocial Assessment Tool (EPAT): from 'what' to 'how' of psychosocial screening - a pilot study.

Thorough psychosocial screening of donor candidates is required in order to minimize potential negative consequences and to strive for optimal safety within living donation programmes. We aimed to develop an evidence-based tool to standardize the psychosocial screening process. Key concepts of psychosocial screening were used to structure our tool: motivation and decision-making, personal resources, psychopathology, social resources, ethical and legal factors and information and risk processing.

Tremor stability index: a new tool for differential diagnosis in tremor syndromes.

See Vidailhet et al. (doi:10.1093/brain/awx140) for a scientific commentary on this article.

The design of a theory-based intervention to improve medication adherence in chronic pain patients.

Objective: Non-adherence to pain medication is common in chronic pain patients and may result in unfavorable treatment outcomes. Interventions to improve adherence behavior often fail to significantly change medication use. In this report, we describe the application of a theoretical psychological model of behavior change in order to design an intervention to improve medication adherence in chronic pain patients.

Genome-independent hypoxic repression of estrogen receptor alpha in breast cancer cells.

Background: About 75-80% of breast tumors express the estrogen receptor alpha (ER-α) and are treated with endocrine-target therapeutics, making this the premier therapeutic modality in the breast cancer clinic. However, acquired resistance is common and about 20% of resistant tumors loose ER-α expression via unknown mechanisms. Inhibition of ER-α loss could improve endocrine therapeutic efficacy, benefiting a significant number of patients.