Unmet Needs and Treatment Preference of Systemic Treatments for Moderate-to-Severe Psoriasis from the Perspectives of Patients and Dermatologists in China.

INTRODUCTION: The treatment options for moderate to severe psoriasis (msPsO) in China have been greatly increased with the approvals of biologics. However, the unmet needs and treatment preferences of systemic treatments for msPsO in China remain unclarified. METHODS: Fifty dermatologists and 300 patients with msPsO (41% with severe psoriasis) were surveyed for effectiveness, safety, treatment convenience, and treatment preferences (using a choice-based conjoint questionnaire). Descriptive statistics and conjoint simulation analyses were employed to summarize survey information and assess treatment preferences. RESULTS: Both patients and dermatologists reported shorter treatment duration for oral drugs (2.7-6.2 months) than that for biologics (9.5-17.0 months). The most frequently reported treatment discontinuation reasons by the surveyed patients and dermatologists were unsatisfactory effectiveness (average 84.5%) for oral drugs and loss of efficacy over time (average 68.5%) for biologics. Commonly reported treatment inconveniences included regular lab tests for traditional oral drugs (average 71.5%) and administration assistance for biologics (average 58.0%). Injection site reactions (average 51.5%) and needle fear (average 35.5%) were frequently reported for biologics among the surveyed patients and dermatologists. Once-daily oral treatment was preferred over biweekly subcutaneous injection treatment when the two had comparable attributes (average in patients 87.1% vs. 12.9%; average in dermatologists 93.4% vs. 6.6%). CONCLUSIONS: Unmet needs of systemic treatments remain for msPsO in China. Once-daily oral treatment is preferred over biweekly subcutaneous injections to treat msPsO when other treatment attributes are comparable.

Accelerating diabetic wound healing by ROS-scavenging lipid nanoparticle-mRNA formulation.

Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care.

Engineering LNPs with polysarcosine lipids for mRNA delivery.

Since the approval of the lipid nanoparticles (LNP)-mRNA vaccines against the SARS-CoV-2 virus, there has been an increased interest in the delivery of mRNA through LNPs. However, current LNP formulations contain PEG lipids, which can stimulate the generation of anti-PEG antibodies. The presence of these antibodies can potentially cause adverse reactions and reduce therapeutic efficacy after administration. Given the widespread deployment of the COVID-19 vaccines, the increased exposure to PEG may necessitate the evaluation of alternative LNP formulations without PEG components. In this study, we investigated a series of polysarcosine (pSar) lipids as alternatives to the PEG lipids to determine whether pSar lipids could still provide the functionality of the PEG lipids in the ALC-0315 and SM-102 LNP systems. We found that complete replacement of the PEG lipid with a pSar lipid can increase or maintain mRNA delivery efficiency and exhibit similar safety profiles in vivo.

Dioscin decreases M2 polarization via inhibiting a positive feedback loop between RBM47 and NF-κB in glioma.

BACKGROUND: The role of the glioblastoma (GBM) microenvironment is pivotal in the development of gliomas. Discovering drugs that can traverse the blood-brain barrier and modulate the tumor microenvironment is crucial for the treatment of GBM. Dioscin, a steroidal saponin derived from various kinds of plants and herbs known to penetrate the blood-brain barrier, has shown its powerful anti-tumor activity. However, little is known about its effects on GBM microenvironment. METHODS: Bioinformatics analysis was conducted to assess the link between GBM patients and their prognosis. Multiple techniques, including RNA sequencing, immunofluorescence staining, Western blot analysis, RNA-immunoprecipitation (RIP) assays, and Chromatin immunoprecipitation (CHIP) analysis were employed to elucidate the mechanism through which Dioscin modulates the immune microenvironment. RESULTS: Dioscin significantly impaired the polarization of macrophages into the M2 phenotype and enhanced the phagocytic ability of macrophages in vitro and in vivo. A strong correlation between high expression of RBM47 in GBM and a detrimental prognosis for patients was demonstrated. RNA-sequencing analysis revealed an association between RBM47 and the immune response. The inhibition of RBM47 significantly impaired the recruitment and polarization of macrophages into the M2 phenotype and enhanced the phagocytic ability of macrophages. Moreover, RBM47 could stabilize the mRNA of inflammatory genes and enhance the expression of these genes by activating the NF-κB pathway. In addition, NF-κB acts as a transcription factor that enhances the transcriptional activity of RBM47. Notably, we found that Dioscin could significantly inhibit the activation of NF-κB and then downregulate the expression of RBM47 and inflammatory genes protein. CONCLUSION: Our study reveals that the positive feedback loop between RBM47 and NF-κB could promote immunosuppressive microenvironment in GBM. Dioscin effectively inhibits M2 polarization in GBM by disrupting the positive feedback loop between RBM47 and NF-κB, indicating its potential therapeutic effects in GBM treatment.

Cryo-EM structure of SRP68/72 reveals an extended dimerization domain with RNA-binding activity.

The signal recognition particle (SRP) is a critical component in protein sorting pathways in all domains of life. Human SRP contains six proteins bound to the 7S RNA and their structures and functions have been mostly elucidated. The SRP68/72 dimer is the largest SRP component and is essential for SRP function. Although the structures of the SRP68/72 RNA binding and dimerization domains have been previously reported, the structure and function of large portions of the SRP68/72 dimer remain unknown. Here, we analyse full-length SRP68/72 using cryo-EM and report that SRP68/72 depend on each other for stability and form an extended dimerization domain. This newly observed dimerization domain is both a protein- and RNA-binding domain. Comparative analysis with current structural models suggests that this dimerization domain undergoes dramatic translocation upon SRP docking onto SRP receptor and eventually comes close to the Alu domain. We propose that the SRP68/72 dimerization domain functions by binding and detaching the Alu domain and SRP9/14 from the ribosomal surface, thus releasing elongation arrest upon docking onto the ER membrane.

LNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing.

Adipose stem cells (ASCs) have attracted considerable attention as potential therapeutic agents due to their ability to promote tissue regeneration. However, their limited tissue repair capability has posed a challenge in achieving optimal therapeutic outcomes. Herein, we conceive a series of lipid nanoparticles to reprogram ASCs with durable protein secretion capacity for enhanced tissue engineering and regeneration. In vitro studies identify that the isomannide-derived lipid nanoparticles (DIM1T LNP) efficiently deliver RNAs to ASCs. Co-delivery of self-amplifying RNA (saRNA) and E3 mRNA complex (the combination of saRNA and E3 mRNA is named SEC) using DIM1T LNP modulates host immune responses against saRNAs and facilitates the durable production of proteins of interest in ASCs. The DIM1T LNP-SEC engineered ASCs (DS-ASCs) prolong expression of hepatocyte growth factor (HGF) and C-X-C motif chemokine ligand 12 (CXCL12), which show superior wound healing efficacy over their wild-type and DIM1T LNP-mRNA counterparts in the diabetic cutaneous wound model. Overall, this work suggests LNPs as an effective platform to engineer ASCs with enhanced protein generation ability, expediting the development of ASCs-based cell therapies.

Meaningful Change Thresholds for the Psoriasis Symptoms and Signs Diary: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Change from baseline score on the validated Psoriasis Symptoms and Signs Diary (PSSD) is a widely used, patient-reported end point in clinical trials for psoriasis. Meaningful score change thresholds anchored to patient-reported assessments have not been established in a clinical trial setting. Objective: To evaluate meaningful within-patient score change thresholds for the PSSD using data from the phase 3 Program to Evaluate the Efficacy and Safety of Deucravacitinib, a Selective TYK2 Inhibitor (POETYK), PSO-1 clinical trial, which compared the efficacy and safety of deucravacitinib vs placebo and apremilast among adults with moderate to severe plaque psoriasis. Design, Setting, and Participants: In this predefined analysis using data from the POETYK PSO-1 multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, conducted from August 7, 2018, to September 2, 2020, 666 adults with moderate to severe plaque psoriasis completed the PSSD daily throughout the trial. Meaningful change thresholds were derived by anchoring mean PSSD score change from baseline to week 16 to category improvements on the Patient Global Impression of Change (PGI-C) and the Patient Global Impression of Severity (PGI-S). Interventions: Deucravacitinib, 6 mg, once daily; placebo; or apremilast, 30 mg, twice daily. Main Outcome and Measures: The main outcome was score change from baseline to week 16 on the PSSD, anchored to the PGI-C and PGI-S. Results: The trial included 666 patients (mean [SD] age, 46.1 [13.4] years; 453 men [68.0%]). Three thresholds were identified using an analysis set of 609 patients. Score improvement of at least 15 points from baseline reflected meaningful within-patient change anchored to the PGI-C. Score improvements of 25 points were supported by both the PGI-C and the PGI-S, while a 30-point score change identified patients with greater improvements in their psoriasis symptoms and signs. Conclusions and Relevance: This analysis suggests that PSSD score improvements of 15, 25, or 30 points represent increasing improvements in disease burden that are meaningful to patients with psoriasis.

Multitask joint learning with graph autoencoders for predicting potential MiRNA-drug associations.

The occurrence of many diseases is associated with miRNA abnormalities. Predicting potential drug-miRNA associations is of great importance for both disease treatment and new drug discovery. Most computation-based approaches learn one task at a time, ignoring the information contained in other tasks in the same domain. Multitask learning can effectively enhance the prediction performance of a single task by extending the valid information of related tasks. In this paper, we presented a multitask joint learning framework (MTJL) with a graph autoencoder for predicting the associations between drugs and miRNAs. First, we combined multiple pieces of information to construct a high-quality similarity network of both drugs and miRNAs and then used a graph autoencoder (GAE) to learn their embedding representations separately. Second, to further improve the embedding quality of drugs, we added an auxiliary task to classify drugs using the learned representations. Finally, the embedding representations of drugs and miRNAs were linearly transformed to obtain the predictive association scores between them. A comparison with other state-of-the-art models shows that MTJL has the best prediction performance, and ablation experiments show that the auxiliary task can enhance the embedding quality and improve the robustness of the model. In addition, we show that MTJL has high utility in predicting potential associations between drugs and miRNAs by conducting two case studies.

Adoptive cell therapy for cancer treatment.

Adoptive cell therapy (ACT) is a rapidly growing anti-cancer strategy that has shown promise in treating various cancer types. The concept of ACT involves activating patients' own immune cells ex vivo and then transferring them back to the patients to recognize and eliminate cancer cells. Currently, the commonly used ACT includes tumor-infiltrating lymphocytes (TILs), genetically engineered immune cells, and dendritic cells (DCs) vaccines. With the advancement of cell culture and genetic engineering techniques, ACT has been used in clinics to treat malignant hematological diseases and many new ACT-based regimens are in different stages of clinical trials. Here, representative ACT approaches are introduced and the opportunities and challenges for clinical translation of ACT are discussed.

Short-, Mid-, and Long-Term Efficacy of Deucravacitinib Versus Biologics and Nonbiologics for Plaque Psoriasis: A Network Meta-Analysis.

INTRODUCTION: Deucravacitinib, a newly approved oral medication for the treatment of patients with moderate to severe plaque psoriasis, demonstrated efficacy versus apremilast and placebo in two phase 3 randomized controlled trials (RCTs). A systematic review and network meta-analysis (NMA) indirectly compared deucravacitinib with other relevant systemic biologic/nonbiologic treatments. METHODS: Online databases were searched for RCTs published through October 2021. Eligible studies were head-to-head comparisons between systemic therapies and/or placebo reporting 50%, 75%, 90%, or 100% improvement in Psoriasis Area and Severity Index (PASI) from baseline in adults with moderate to severe plaque psoriasis. Comparisons included tumor necrosis factor inhibitors, interleukin (IL)-17, IL-23, and IL 12/23 inhibitors, and systemic nonbiologics. A multinomial Bayesian NMA was used to derive estimates of the relative efficacy of deucravacitinib and other systemic therapies. Response probabilities for each treatment and corresponding 95% credible intervals (CrIs) for achieving a PASI response were calculated over short-, mid-, and long-term follow-up (weeks 10-16, 24-28, and 44-60). RESULTS: The NMA included 47 RCTs. Deucravacitinib showed the highest PASI 75 response rates among nonbiologic systemic therapies across time points. Deucravacitinib PASI 75 response rate (95% CrI) over short-term follow-up was 54.1% (46.5-61.6), within the range of first-generation biologics (etanercept, 39.7% [31.6-48.3]; infliximab, 79.0% [74.0-83.5]). At mid-term follow-up, deucravacitinib PASI 75 increased to 63.3% (58.0-68.4). At long-term follow-up, deucravacitinib PASI 75 was 65.9% (58.0-73.4), comparable to first-generation biologics adalimumab (62.8%; 55.3-69.6) and ustekinumab (68.0%; 64.6-71.5). CONCLUSIONS: Patients receiving deucravacitinib were more likely to achieve PASI 75 response versus apremilast and methotrexate across all time points. The long-term PASI 75 response rate for deucravacitinib was similar to those of adalimumab and ustekinumab. The approval of deucravacitinib offers patients the choice of an oral therapy with long-term efficacy similar to that of some biologics.

Close the cancer-immunity cycle by integrating lipid nanoparticle-mRNA formulations and dendritic cell therapy.

Effective cancer immunotherapy is usually blocked by immunosuppressive factors in the tumour microenvironment, resulting in tumour promotion, metastasis and recurrence. Here we combine lipid nanoparticle-mRNA formulations and dendritic cell therapy (named CATCH) to boost the cancer-immunity cycle via progressive steps to overcome the immunosuppressive tumour microenvironment. Multiple types of sugar-alcohol-derived lipid nanoparticles are conceived to modulate the cancer-immunity cycle. First, one type of lipid nanoparticle containing CD40 ligand mRNA induces robust immunogenic cell death in tumoural tissues, leading to the release of tumour-associated antigens and the expression of CD40 ligand. Next, dendritic cells engineered by another type of lipid nanoparticle encapsulating CD40 mRNA are adoptively transferred, which are then activated by the CD40 ligand molecules in tumoural tissues. This promotes the secretion of multiple cytokines and chemokines, and the upregulation of co-stimulatory molecules on dendritic cells, which are crucial for reprogramming the tumour microenvironment and priming the T-cell responses. After dendritic cells present tumour-associated antigens to T cells, all the above stepwise events contribute to boosting a potent tumour-specific T-cell immunity that eradicates established tumours, suppresses distal lesions and prevents tumour rechallenge.

Suboptimal Clinical and Quality of Life Outcomes in Patients with Psoriasis Undertreated with Oral Therapies: International Physician and Patient Survey.

INTRODUCTION: Psoriasis is a chronic, inflammatory, immune-mediated disease. This study assessed the time at which patients switched from a conventional oral systemic treatment to a biologic therapy; patient clinical and quality of life (QoL) outcomes associated with oral systemic treatments; and the proportion of patients who persisted on oral therapy (nonswitchers), despite reported suboptimal clinical and QoL outcomes. METHODS: This data analysis used the Adelphi Real World Psoriasis Disease Specific Programme, a non-interventional, retrospective, cross-sectional survey conducted in the USA, France, Germany, and United Kingdom (August 2018-April 2019). Kaplan-Meier (KM) analysis assessed switching from oral to biologic therapy in patients treated ≥ 3 years at survey completion (n = 597). The severity of psoriasis was reported by physicians as the percentage of body surface area (BSA) affected by psoriasis. Dermatology Life Quality Index (DLQI) scores were calculated for three groups: nonswitchers who met treatment failure criteria, nonswitchers who did not meet failure criteria, and switchers to a biologic therapy. RESULTS: In KM analysis, approximately 50% of the patient population switched by 24 months. A substantial portion of nonswitchers continued to have moderate-to-severe psoriasis. Among nonswitchers, 57-77% had BSA ≥ 3% and 16-24% had BSA ≥ 10% at the time of the survey compared with 37% of switchers who had BSA of ≥ 3% and 9% who had BSA of ≥ 10%. QoL was poor among nonswitchers. The mean [standard deviation (SD)] DLQI scores for nonswitchers meeting treatment failure criteria, nonswitchers not meeting failure criteria, and switchers were 6.11 (4.55), 2.62 (3.29), and 2.25 (4.23), respectively. CONCLUSION: There is a clear unmet need for more effective oral therapies, and further research into the reasons for patients remaining undertreated, which may include patient preference for oral treatments (despite lack of response), contraindications, or insurance/formulary-related barriers to access, are needed.

Psoriasis is a common skin disease that causes itchy, painful, scaly sores. Patients may feel stigmatized, which can impact their quality of life and productivity. About 1 in 5 patients have severe psoriasis, which is harder to treat and may require pills or shots. Both shots and pills are effective at treating psoriasis; however, many patients choose to continue taking pills, even if their psoriasis worsens, for reasons including a desire to avoid needles. We described patients with moderate-to-severe psoriasis who started on pills and either remained on pills or switched to shots by the time of the survey. We looked at the reasons they gave for switching, as well as at quality of life measures reported by the patients. To do this, we analyzed data from a survey called the Adelphi Real World Psoriasis Disease Specific Programme. This survey was conducted among doctors who treat skin diseases and their patients. Participating doctors and patients from the USA, France, Germany, and the United Kingdom were asked questions about the patients' health and how psoriasis affects their lives. Survey results showed that nearly half of patients switched to shots by 24 months, and most who switched cited treatment failure as the reason. Those who continued to take their pills despite having more severe psoriasis symptoms had more itching and pain and had lower quality of life than those who switched to shots. This suggests that there is a need for more effective oral treatments for patients with psoriasis.

mRNA delivery in cancer immunotherapy.

Messenger RNA (mRNA) has drawn much attention in the medical field. Through various treatment approaches including protein replacement therapies, gene editing, and cell engineering, mRNA is becoming a potential therapeutic strategy for cancers. However, delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake. Therefore, in addition to mRNA modification, efforts have been devoted to developing nanoparticles for mRNA delivery. In this review, we introduce four categories of nanoparticle platform systems: lipid, polymer, lipid-polymer hybrid, and protein/peptide-mediated nanoparticles, together with their roles in facilitating mRNA-based cancer immunotherapies. We also highlight promising treatment regimens and their clinical translation.

Variables associated with joint involvement and development of a prediction rule for arthritis in patients with psoriasis. An analysis of the Italian PsoReal database.

BACKGROUND: Limited data exist to predict the development of psoriatic arthritis (PsA) in patients with psoriasis (PsO). OBJECTIVE: To analyze factors associated with incident PsA in patients with PsO, and to develop a predictive algorithm for progression to arthritis using a full set of variables and a restricted one applicable to administrative data. METHODS: Cohort study within the PsoReal registry in Italy. Multivariable generalized linear models were used to assess factors associated with PsA and to derive a predictive model. RESULTS: Among 8895 patients, 226 PsA cases were identified (incidence 1.9 per 100 patient-years). Independent predictors in the full model were as follows: female sex, age 40 to 59 years, body mass index ≥ 25, chronic-plaque PsO features, presence of palmoplantar pustulosis, hospitalization for PsO in the last 5 years, and previous use of systemic PsO therapy (area under the receiver operating characteristic curve = 0.74). Female sex, age 40 to 59 years, hospitalization for PsO, and previous use of systemic PsO therapy were independent predictors in the restricted model (area under the receiver operating characteristic curve = 0.72). LIMITATIONS: Lack of other potential predictors for PsA. CONCLUSION: Our models could be used by clinicians and health authorities when planning intervention and population surveillance. Future studies should confirm our models using larger datasets and additional variables.

STING Agonist-Derived LNP-mRNA Vaccine Enhances Protective Immunity Against SARS-CoV-2.

Lipid nanoparticle (LNP)-mediated delivery of messenger RNA (mRNA) COVID-19 vaccines has provided large-scale immune protection to the public. To elicit a robust immune response against SARS-CoV-2 infections, antigens produced by mRNAs encoding SARS-CoV-2 Spike glycoprotein need to be efficiently delivered and presented to antigen-presenting cells such as dendritic cells (DCs). As concurrent innate immune stimulation can facilitate the antigen presentation process, a library of non-nucleotide STING agonist-derived amino lipids (SALs) was synthesized and formulated into LNPs for mRNA delivery. SAL12 lipid nanoparticles (SAL12-LNPs) were identified as most potent in delivering mRNAs encoding the Spike glycoprotein (S) of SARS-CoV-2 while activating the STING pathway in DCs. Two doses of SAL12 S-LNPs by intramuscular immunization elicited potent neutralizing antibodies against SARS-CoV-2 in mice.

Real-world treatment patterns and healthcare costs in patients with psoriasis taking systemic oral or biologic therapies.

BACKGROUND: Psoriasis is a chronic, immune-mediated, systemic inflammatory disorder associated with high costs. This study evaluated real-world treatment patterns and associated costs in patients in the United States with psoriasis initiating systemic oral or biologic treatments. METHODS: This retrospective cohort study used IBM® (now Merative™) MarketScan® Commercial and Medicare claims (1 January 2006-31 December 2019) to evaluate patterns of switching, discontinuation, and nonswitching in two cohorts of patients initiating oral or biologic systemic therapy. Total pre-switch and post-switch costs were reported per-patient per-month (PPPM). RESULTS: Each cohort was analyzed (oral, n = 11,993; biologic; n = 9753). Among the oral and biologic cohorts, 32% and 15% discontinued index and any systemic treatment within 1 year of initiation; 40% and 62% remained on index therapy; and 28% and 23% switched treatment, respectively. In the oral and biologic cohorts, total PPPM costs within 1 year of initiation for nonswitchers, patients who discontinued, and patients who switched were $2594, $1402, and $3956, respectively, and $5035, $3112, and $5833, respectively. CONCLUSION: This study identified lower persistence in the oral treatment cohort, higher costs associated with switching, and a need for safe and effective oral treatment options for patients with psoriasis to delay the switch to biologic therapy.

A discrete choice experiment on oral and injection treatment preferences among moderate-to-severe psoriasis patients in Japan.

Long-term psoriasis (PsO) management remains challenging. With growing variation in treatment efficacy, cost, and modes of administration, patient preferences for different treatment characteristics are not well understood. A discrete choice experiment (DCE), informed by qualitative patient interviews, was conducted to assess patient preferences for different attributes of PsO treatments; 222 adult patients with moderate-to-severe PsO receiving systemic therapy participated in the DCE web survey. Better long-term efficacy and lower cost were preferred (preference weights p < 0.05). Long-term efficacy had the highest relative importance (RI) and mode of administration was as important as the outcome attributes (efficacy and safety). Patients also preferred oral to injectable administration. In subgroup analyses by disease severity, residence, psoriatic arthritis as a comorbidity, and gender, the trends for each subgroup were the same as the overall population although the extent of RI for administration mode varied. Mode of administration was more important for patients with moderate versus severe disease, or rural versus urban residence. This DCE utilized attributes related to both oral and injectable treatment as well as a broad study population of systemic treatment users. Preferences were further stratified by patient characteristics to explore trends in different subgroups. Understanding the RI of treatment attributes and the attribute trade-offs acceptable to patients helps inform moderate-to-severe PsO systemic treatments decisions.

The role of auxiliary domains in modulating CHD4 activity suggests mechanistic commonality between enzyme families.

CHD4 is an essential, widely conserved ATP-dependent translocase that is also a broad tumour dependency. In common with other SF2-family chromatin remodelling enzymes, it alters chromatin accessibility by repositioning histone octamers. Besides the helicase and adjacent tandem chromodomains and PHD domains, CHD4 features 1000 residues of N- and C-terminal sequence with unknown structure and function. We demonstrate that these regions regulate CHD4 activity through different mechanisms. An N-terminal intrinsically disordered region (IDR) promotes remodelling integrity in a manner that depends on the composition but not sequence of the IDR. The C-terminal region harbours an auto-inhibitory region that contacts the helicase domain. Auto-inhibition is relieved by a previously unrecognized C-terminal SANT-SLIDE domain split by ~150 residues of disordered sequence, most likely by binding of this domain to substrate DNA. Our data shed light on CHD4 regulation and reveal strong mechanistic commonality between CHD family members, as well as with ISWI-family remodellers.

Cost Effectiveness of Adding Pembrolizumab to Platinum and Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Esophageal Cancer: A US Healthcare Payer's Perspective.

BACKGROUND AND OBJECTIVE: Pembrolizumab plus cisplatin and fluorouracil demonstrated superior efficacy and comparable safety compared with fluorouracil and cisplatin (FP) as first-line treatment for locally advanced unresectable or metastatic carcinoma of the esophagus and gastroesophageal junction adenocarcinoma in a phase III trial (KEYNOTE-590). This study evaluated the cost effectiveness of pembrolizumab plus FP versus FP and versus a blended chemotherapy comparator including FP, carboplatin plus paclitaxel, FOLFOX, FOLFIRI, docetaxel plus FP, trastuzumab plus FP, and trastuzumab plus FOLFOX from a US healthcare payer's perspective. METHODS: A partitioned survival model was developed with three health states (progression-free, progressive disease, and death). Overall survival, progression-free survival, time on treatment, and adverse events were informed by patient-level data from KEYNOTE-590. The blended chemotherapy comparator reflected the current US treatment landscape and was assumed to have similar efficacy and safety as FP. Health utilities were estimated using linear mixed-effects models based on EQ-5D-5L data from the trial. Resource use and cost inputs (2020 US dollars) were based on US standard sources and literature. Costs, life-years, and quality-adjusted life-years (QALYs) discounted at 3.0% per year and incremental cost-effectiveness ratio were outcomes in the model. Sensitivity and scenario analyses were conducted to assess the robustness of base-case results. RESULTS: Compared with FP, pembrolizumab plus FP produced a mean gain of 0.86 life-year and 0.77 QALY with additional costs of $112,630 over 37.6 years, yielding an incremental cost-effectiveness ratio of $147,097 per QALY. Results were similar when the intervention was pembrolizumab plus alternative chemotherapies or when blended chemotherapy became the comparator. Results were most sensitive to different overall survival extrapolation approaches. CONCLUSIONS: Our analysis suggests that pembrolizumab plus chemotherapy extended life-years and QALYs and is cost effective compared with chemotherapy alone as a first-line treatment for advanced esophageal cancer in the USA given a willingness-to-pay threshold of $150,000 per QALY.