Study Protocol: Predicting the Quality of Response to Specific Treatments (PQRST) in Chronic Graft-versus-Host Disease.

BACKGROUND: Chronic graft-versus-host disease (GVHD) is a leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Despite significant progress in chronic GVHD therapies, challenges remain in understanding pleomorphic phenotypes and varying response to treatment. The goal of the Predicting the Quality of Response to Specific Treatments (PQRST) in chronic GVHD study is to identify predictors of treatment response. This report describing the study design seeks to raise awareness and invite collaborations with investigators who wish to access clinical data and research samples from this study. METHODS: This is a prospective, observational cohort study involving data collection from patients who are beginning first-, second-, or third-line systemic therapy for chronic GVHD with defined agents. Evaluable participants will have baseline assessments and research samples prior to starting the index therapy, and 1 month after starting treatment. Response assessments occur at 3 and 6 months after start of treatment, or if a new systemic therapy is started before 6 months. Target enrollment is approximately 200 patients at 8 institutions, with at least 6 months of follow up to determine response to index therapy. RESULTS: Enrollment started in July 2020 and was delayed due to the COVID-19 pandemic; as of 3/1/2024, 137 evaluable participants have been enrolled. DISCUSSION: The Chronic GVHD Consortium "PQRST" is a large longitudinal cohort study that aims to investigate predictors of treatment response by identifying biologically and clinically defined patient subgroups. We welcome investigators to collaborate in the use of these data. TRIAL REGISTRATION: NCT04431479.

Role of hematological and neurological expressed 1 (HN1) in Human Cancers.

Hematological and neurological expressed 1 (HN1), also known as Jupiter microtubule associated homolog 1 (JPT1), is a highly conserved protein with widespread expression in various tissues. Ectopic elevation of HN1 has been observed in multiple cancers, highlighting its role in tumorigenesis and progression. Both proteomics and transcriptomics reveal that HN1 is closely associated with severe disease progression, poor prognostic and shorter overall survival. HN1's involvement in cancer cell proliferation and metastasis has been extensively investigated. Overexpression of HN1 is associated with increased tumor growth and disease progression, while its depletion leads to cell cycle arrest and apoptosis. The pivotal role of HN1 in cancer progression, particularly in proliferation, migration, and invasion, underscores its significance in cancer metastasis. Validation of the efficacy and safety of HN1 inhibition, along with the development of diagnostic methods to determine HN1 expression levels in patients, is essential for the translation of HN1-targeted therapies into clinical practice. Overall, HN1 emerges as a valuable prognostic marker and therapeutic target in cancer, and further investigations hold the potential to improve patient outcomes by impeding metastasis and enhancing treatment strategies.

Comparison of treatment response measures in cutaneous sclerosis after allogeneic hematopoietic cell transplantation.

Cutaneous sclerosis, a highly morbid subtype of chronic graft vs. host disease (cGVHD), demonstrates limited treatment response under current NIH Response Measures. We explored novel sclerosis-specific response measures using Chronic GVHD Consortium data. A training cohort included patients with cutaneous sclerosis from a randomized trial of imatinib vs. rituximab, and a Consortium observational study. The validation cohort was a different Consortium observational study. Clinician-reported measures (baseline, and baseline to 6-month change) were examined for association with 6-month clinician-reported response. Patient-reported measures (baseline and baseline to 6-month change) were studied for association with 6-month patient-reported response. A total of 347 subjects were included (training 183, validation 164). While multiple skin and joint measures were associated with clinician-reported response on univariate analysis, PROM total score, PROM total score change, and NIH 0-3 skin change were retained in the final multivariate model (AUC 0.83 training, 0.75 validation). Similarly, many patient-reported measures were associated, but final multivariate analysis retained the HAP AAS, SF36 vitality change, LSS skin, and LSS skin change in the model (AUC 0.86 training, 0.75 validation). We identified which sclerosis measures have greatest association with 6-month clinician- and patient-reported treatment response, a previously unstudied area. However, given the observed performance in the validation cohorts, we conclude that further work is needed. Novel response measures may be needed to optimally assess treatment response in cutaneous sclerosis.

Neural topic models with survival supervision: Jointly predicting time-to-event outcomes and learning how clinical features relate.

We present a neural network framework for learning a survival model to predict a time-to-event outcome while simultaneously learning a topic model that reveals feature relationships. In particular, we model each subject as a distribution over "topics", where a topic could, for instance, correspond to an age group, a disorder, or a disease. The presence of a topic in a subject means that specific clinical features are more likely to appear for the subject. Topics encode information about related features and are learned in a supervised manner to predict a time-to-event outcome. Our framework supports combining many different topic and survival models; training the resulting joint survival-topic model readily scales to large datasets using standard neural net optimizers with minibatch gradient descent. For example, a special case is to combine LDA with a Cox model, in which case a subject's distribution over topics serves as the input feature vector to the Cox model. We explain how to address practical implementation issues that arise when applying these neural survival-supervised topic models to clinical data, including how to visualize results to assist clinical interpretation. We study the effectiveness of our proposed framework on seven clinical datasets on predicting time until death as well as hospital ICU length of stay, where we find that neural survival-supervised topic models achieve competitive accuracy with existing approaches while yielding interpretable clinical topics that explain feature relationships. Our code is available at: https://github.com/georgehc/survival-topics.

Strategies for Accelerated Drug Development: An Industry Perspective Based on an IQ Consortium Survey of CMC Considerations.

Over the past decade, there has been an increase in accelerated drug development with successful regulatory approval that has provided rapid access of novel medicines to patients world-wide. This has created the opportunity for the pharmaceutical industry to continuously improve the process of quickly bringing new medicines to patients with unmet medical needs. This can be accomplished through sharing the learnings and advancements in drug development, enhancing regulatory interactions, and collaborating with academics on developing the underlying science to reduce drug development timelines. In this paper, the IQ Consortium - Accelerated Drug Development working group members intend to share recommendations for optimizing strategies that build efficiencies in accelerated pathways for regulatory approval. Information was obtained by surveying member pharmaceutical companies with respect to recent expedited submissions within the past 5 years to gain insights as to which development strategies were successful. The learnings from this analysis are provided, which includes shared learnings in formulation development, stability, analytical methods, manufacturing, and importation testing as well as regulatory considerations. Each of these sections provide a summary illustrating the key data collected as well as a discussion that is aimed to guide pharmaceutical companies on strategies to consider streamlining development activities and expedite the drug to market.

Impact of nutrient deficiency on biological sewage treatment - Perspectives towards urine source segregation.

Human urine contains 9 g/L of nitrogen (N) and 0.7 g/L of phosphorus (P). The recovery of N and P from urine helps close the nutrient loop and increase resource circularity in the sewage treatment sector. Urine contributes an average of 80 % N and 50 % P in sewage, whereby urine source segregation could reduce the burden of nutrient removal in sewage treatment plants (STPs) but result in N and P deficiency and unintended negative consequences. This review examines the potential impacts of N and P deficiency on the removal of organic carbon and nutrients, sludge characteristics and greenhouse gas emissions in activated sludge processes. The details of how these impacts affect the operation of STPs were also included. This review helps foresee operational challenges that established STPs may face when dealing with nutrient-deficient sewage in a future where source separation of urine is the norm. The findings indicate that the requirement of nitrification-denitrification and biological P removal processes could shrink at urine segregation above 80 % and 100 %, respectively. Organic carbon, N and biological P removal processes can be severely affected under full urine segregation. The decrease in solid retention time due to urine segregation increases treatment capacity up to 48 %. Sludge flocculation and settleability would deteriorate due to changes in extracellular polymeric substances and induce various forms of bulking. Beneficially, N deficiency reduces nitrous oxide emissions. These findings emphasise the importance of considering and preparing for impacts caused by urine source segregation-induced nutrient deficiency in sewage treatment processes.

Study protocol: Close Assessment and Testing for Chronic Graft-vs.-Host disease (CATCH).

Chronic graft-versus-host disease (GVHD) is an immune-mediated disorder that causes significant late morbidity and mortality following allogeneic hematopoietic cell transplantation. The "Close Assessment and Testing for Chronic GVHD (CATCH)" study is a multi-center Chronic GVHD Consortium prospective, longitudinal cohort study designed to enroll patients before hematopoietic cell transplantation and follow them closely to capture the development of chronic GVHD and to identify clinical and biologic biomarkers of chronic GVHD onset. Data are collected pre-transplant and every two months through one-year post-transplant with chart review thereafter. Evaluations include clinician assessment of chronic GVHD and its manifestations, patient-reported outcomes, multiple biospecimens (blood, saliva, tears, buccal mucosa and fecal samples, biopsies of skin and mouth), laboratory testing, and medical record abstraction. This report describes the rationale, design, and methods of the CATCH study, and invites collaboration with other investigators to leverage this resource. trial registration: This study is registered at www.clinicaltrials.gov as NCT04188912.

Demonstration of a low loss, highly stable and re-useable edge coupler for high heralding efficiency and low g(2)(0) SOI correlated photon pair sources.

We report a stable, low loss method for coupling light from silicon-on-insulator (SOI) photonic chips into optical fibers. The technique is realized using an on-chip tapered waveguide and a cleaved small core optical fiber. The on-chip taper is monolithic and does not require a patterned cladding, thus simplifying the chip fabrication process. The optical fiber segment is composed of a centimeter-long small core fiber (UHNA7) which is spliced to SMF-28 fiber with less than -0.1 dB loss. We observe an overall coupling loss of -0.64 dB with this design. The chip edge and fiber tip can be butt coupled without damaging the on-chip taper or fiber. Friction between the surfaces maintains alignment leading to an observation of ±0.1 dB coupling fluctuation during a ten-day continuous measurement without use of any adhesive. This technique minimizes the potential for generating Raman noise in the fiber, and has good stability compared to coupling strategies based on longer UHNA fibers or fragile lensed fibers. We also applied the edge coupler on a correlated photon pair source and observed a raw coincidence count rate of 1.21 million cps and raw heralding efficiency of 21.3%. We achieved an auto correlation function g H(2)(0) as low as 0.0004 at the low pump power regime.

Enhancer-targeted CRISPR-Activation Rescues Haploinsufficient Autism Susceptibility Genes.

Autism Spectrum Disorder (ASD) is a highly heritable condition with diverse clinical presentations. Approximately 20% of ASD's genetic susceptibility is imparted by de novo mutations of major effect, most of which cause haploinsufficiency. We mapped enhancers of two high confidence autism genes - CHD8 and SCN2A and used CRISPR-based gene activation (CRISPR-A) in hPSC-derived excitatory neurons and cerebral forebrain organoids to correct the effects of haploinsufficiency, taking advantage of the presence of a wildtype allele of each gene and endogenous gene regulation. We found that CRISPR-A induced a sustained increase in CHD8 and SCN2A expression in treated neurons and organoids, with rescue of gene expression levels and mutation-associated phenotypes, including gene expression and physiology. These data support gene activation via targeting enhancers of haploinsufficient genes, as a therapeutic intervention in ASD and other neurodevelopmental disorders.

Clinical and socioeconomic determinants of survival in biliary tract adenocarcinomas.

BACKGROUND: Despite advances in detection and treatments, biliary tract cancers continue to have poor survival outcomes. Currently, there is limited data investigating the significance of socioeconomic status, race/ethnicity, and environmental factors in biliary tract cancer survival. AIM: To investigate how socioeconomic status and race/ethnicity are associated with survival. METHODS: Data from the Surveillance, Epidemiology, and End Results database for biliary and gallbladder adenocarcinomas were extracted from 1975 to 2016. Socioeconomic data included smoking, poverty level, education, adjusted household income, and percentage of foreign-born persons and urban population. Survival was calculated with Cox proportional hazards models for death in the 5-year period following diagnosis. RESULTS: Our study included 15883 gallbladder, 11466 intrahepatic biliary, 12869 extrahepatic biliary and 7268 ampulla of Vater adenocarcinoma cases. When analyzing county-specific demographics, patients from counties with higher incomes were associated with higher survival rates [hazard ratio (HR) = 0.97, P <0.05]. Similarly, counties with a higher percentage of patients with a college level education and counties with a higher urban population had higher 5-year survival rates (HR = 0.96, P = 0.002 and HR = 0.97, P = 0.004, respectively). CONCLUSION: Worse survival outcomes were observed in lower income counties while higher income and education level were associated with higher 5-year overall survival among gallbladder and biliary malignancies.

Mortality in recipients of allogeneic haematopoietic cell transplantation in the era of cytomegalovirus primary prophylaxis: a single-centre retrospective experience.

OBJECTIVES: Allogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes. METHODS: We conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D-/R-, R+/LTV-, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, and relapse up to week 48 after allo-HCT. The D-/R- group served as the reference for comparisons in univariate, competing risk regression, and cumulative incidence functions. RESULTS: The analysis included 1071 consecutive allo-HCT recipients: 131 D-/R-, 557 R+/LTV-, and 383 R+/LTV+. All-cause mortality by day 100 was 6.1% for the D-/R- group, compared with 14.0% (p 0.024) and 7.8% (p 0.7) for the R+/LTV- and R+/LTV + groups, respectively. Non-relapse mortality by day 100 was 11.0%, 6.8% and 3.8% for R+/LTV-, R+/LTV+, and D-/R- groups, respectively, without significant difference. When including relapse as a competing event, the hazard ratio for non-relapse mortality was 1.83 (95% CI: 1.12-2.99, p 0.017) for R+/LTV- compared with D-/R- and 1.05 (95% CI 0.62-1.77, p 0.85) for R+/LTV + compared with D-/R-. DISCUSSION: CMV primary prophylaxis with LTV abrogated the mortality gap based on CMV serostatus, a protective effect that persisted after discontinuation of primary prophylaxis.

Targeting Nrf2 to treat thyroid cancer.

Oxidative stress (OS) is recognized as a contributing factor in the development and progression of thyroid cancer. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor involved in against OS generated by excessive reactive oxygen species (ROS). It governs the expression of a wide array of genes implicated in detoxification and antioxidant pathways. However, studies have demonstrated that the sustained activation of Nrf2 can contribute to tumor progression and drug resistance in cancers. The expression of Nrf2 was notably elevated in papillary thyroid cancer tissues compared to normal tissues, indicating that Nrf2 may play an oncogenic role in the development of papillary thyroid cancer. Nrf2 and its downstream targets are involved in the progression of thyroid cancer by impacting the prognosis and ferroptosis. Furthermore, the inhibition of Nrf2 can increase the sensitivity of target therapy in thyroid cancer. Therefore, Nrf2 appears to be a potential therapeutic target for the treatment of thyroid cancer. This review summarized current data on Nrf2 expression in thyroid cancer, discussed the function of Nrf2 in thyroid cancer, and analyzed various strategies to inhibit Nrf2.

Sodium-iodide symporter and its related solute carriers in thyroid cancer.

The solute carrier (SLC) family is a large group of membrane transport proteins. Their dysfunction plays an important role in the pathogenesis of thyroid cancer. The most well-known SLC is the sodium-iodide symporter (NIS), also known as sodium/iodide co-transporter or solute carrier family 5 member 5 (SLC5A5) in thyroid cancer. The dysregulation of NIS in thyroid cancer is well documented. The role of NIS in the uptake of iodide is critical in the treatment of thyroid cancer, radioactive iodide (RAI) therapy in particular. In addition to NIS, other SLC members may affect the autophagy, proliferation, and apoptosis of thyroid cancer cells, indicating that an alteration in SLC members may affect different cellular events in the evolution of thyroid cancer. The expression of the SLC members may impact the uptake of chemicals by the thyroid, suggesting that targeting SLC members may be a promising therapeutic strategy in thyroid cancer.

High-toughness, extensile and self-healing PDMS elastomers constructed by decuple hydrogen bonding.

Elastomers are widely used in traditional industries and new intelligent fields. However, they are inevitably damaged by electricity, heat, force, etc. during the working process. With the continuous improvement of reliability and environmental protection requirements in human production and living, it is vital to develop elastomer materials with good mechanical properties that are not easily damaged and can self-heal after being damaged. Nevertheless, there are often contradictions between mechanical properties and self-healing as well as toughness, strength, and ductility. Herein, a strong and dynamic decuple hydrogen bonding based on carbon hydrazide (CHZ) is reported, accompanied with soft polydimethylsiloxane (PDMS) chains to prepare self-healing (efficiency 98.7%), recyclable, and robust elastomers (CHZ-PDMS). The strategy of decuple hydrogen bonding will significantly impact the study of the mechanical properties of elastomers. High stretchability (1731%) and a high toughness of 23.31 MJ m-3 are achieved due to the phase-separated structure and energy dissipation. The recyclability of CHZ-PDMS further supports the concept of environmental protection. The application of CHZ-PDMS as a flexible strain sensor exhibited high sensitivity.

Modulating Skeletons of Covalent Organic Framework for High-Efficiency Gold Recovery.

Covalent organic frameworks (COFs) have attracted considerable attention as adsorbents for capturing and separating gold from electronic wastes. To enhance the binding capture efficiency, constructing hydrogen-bond nanotraps along the pore walls was one of the most widely adopted approaches. However, the development of absorbing skeletons was ignored due to the weak binding ability of the gold salts (Au). Herein, we demonstrated skeleton engineering to construct highly efficiently absorbs for Au capture. The strong electronic donating feature of diarylamine units enhanced the electronic density of binding sites (imine-linkage) and thus resulted in high capacities over 1750 mg g-1 for all three COFs. Moreover, the absorbing performance was further improved via the ionization of diarylamine units. The ionic COF achieved 90 % of the maximal adsorption capacity, 1.63 times of that from the charge-neutral COF within ten minutes, and showed remarkable uptakes of 1834 mg g-1 , exceptional selectivity (97.45 %) and cycling stability. The theoretical calculation revealed the binding sites altering from imine bonds to ionic amine sites after ionization of the frameworks, which enabled to bind the AuCl4 - via coulomb force and contributed to enhanced absorbing kinetics. This work inspires us to design molecular/ionic capture based on COFs.

Patient-reported treatment response in chronic graft-versus-host disease.

Chronic graft-versus-host disease (GvHD) treatment response is assessed using National Institutes of Health (NIH) Consensus Criteria in clinical trials, and by clinician assessment in routine practice. Patient-reported treatment response is central to the experience of chronic GvHD manifestations as well as treatment benefit and toxicity, but how they correlate with clinician- or NIH-responses has not been well-studied. We aimed to characterize 6-month patientreported response, determine associated chronic GvHD baseline organ features and changes, and evaluate which patientreported quality of life and chronic GvHD symptom burden measures correlated with patient-reported response. From two nationally representative Chronic GVHD Consortium prospective observational studies, 382 subjects were included in this analysis. Patient and clinician responses were categorized as improved (completely gone, very much better, moderately better, a little better) versus not improved (about the same, a little worse, moderately worse, very much worse). At six months, 270 (71%) patients perceived chronic GvHD improvement, while 112 (29%) perceived no improvement. Patient-reported response had limited correlation with either clinician-reported (kappa 0.37) or NIH chronic GvHD response criteria (kappa 0.18). Notably, patient-reported response at six months was significantly associated with subsequent failure-free survival. In multivariate analysis, NIH responses in eye, mouth, and lung had significant association with 6-month patient-reported response, as well as a change in Short Form 36 general health and role physical domains and Lee Symptom Score skin and eye changes. Based on these findings, patient-reported responses should be considered as an important complementary endpoint in chronic GvHD clinical trials and drug development.