Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD.

Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations1-3. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural-immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex1,2,4-6. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions.

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.

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.

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.

Long-range distributed vibration sensing using phase-sensitive forward optical transmission.

Long-range vibration sensing is an important tool for real-time structural health monitoring. A new, to the best of our knowledge, design of a distributed fiber-optic vibration sensor is introduced and experimentally demonstrated in this study. The proposed system utilizes the transmission of light in the forward direction for sensing, and a self-interference method for laser source simplification. To extract vibration information from phase modulation of light, two Mach-Zehnder interferometers (MZIs) are employed with a 3 × 3 coupler-based differential cross multiplication algorithm for phase calculation. A folded double-ended detection configuration allows the time-of-flight difference via cross correlation (CC) to provide vibration positioning. Experimental results demonstrate a sensing range of up to ∼80 km without optical amplification, accompanied by a position accuracy of 336 m.

Long-range distributed vibration sensing using phase-sensitive forward optical transmission: publisher's note.

This publisher's note contains corrections to Opt. Lett.48, 4825 (2023)10.1364/OL.500587.

Super-long-range distributed vibration sensor based on the polarimetric forward-transmission of light.

Undersea earthquake-triggered giant tsunamis pose significant threats to coastal areas, spanning thousands of kilometers and affecting populations, ecosystems, and infrastructure. To mitigate their impact, monitoring seismic activity in underwater environments is crucial. In this study, we propose a new, to the best of our knowledge, approach for monitoring vibrations in submarine optical cables. By detecting vibration-induced polarization rotation, our dual-wavelength fiber-optic sensing system enables precise measurement of acoustic/vibration amplitude, frequency, and position. As a proof of concept, a double-ended forward-transmission distributed fiber-optic vibration sensor was demonstrated with a single vibration source with a sensitivity of 3.4 mrad/µÎµ at 100 Hz (20 m fiber on PZT), limit of detection of 1.7 pε/Hz1/2 at 100 Hz, sensing range of 121.5 km without an optical amplifier, spatial resolution of 5 m, and position error as small as 34 m. The vibration frequency range tested is from 0.01 to 100 Hz. The sensing system has several advantages, including elegant setup, noise mitigation, and super-long sensing distance.

Durable discontinuation of systemic therapy in patients affected by chronic graft-versus-host disease.

Successful treatment of chronic graft-versus-host disease (GvHD) often requires long-term systemic therapy (ST). Durable discontinuation of ST reflects the resolution of active chronic GvHD. We evaluated the factors associated with durable ST discontinuation, defined as cessation of all ST for ≥12 months, using data from two prospectively followed cohorts from the Chronic GvHD Consortium (n=684). Transplant sources were peripheral blood (89%), bone marrow (6.6%), and cord blood (4.4%) from HLA matched related (37.6%), HLA matched unrelated (45%), and other donor types (18%). Half of the patients received non-myeloablative conditioning. The median time from transplantation to chronic GvHD diagnosis was 7.7 months (range, 1.0-141.3) and the median time from chronic GvHD onset to enrollment into the cohorts was 0.9 months (range, 0.0-12.0). The cumulative incidence estimate of durable ST discontinuation was 32% (95% confidence interval: 28%-37%) at 10 years after enrollment into the cohort. Among patients who discontinued ST, the median time from chronic GvHD diagnosis to durable ST discontinuation was 3.6 years (range, 1.2-10.5). In multivariate analysis, patients who received myeloablative conditioning, had chronic GvHD manifested as moderate/severe lower gastrointestinal involvement, and had a higher (worse) Lee symptom overall score were less likely to attain durable ST discontinuation. In contrast, mild lower gastrointestinal involvement and cord blood (vs. peripheral blood) as the graft source were associated with a greater likelihood of ST discontinuation. Although a minority of patients can discontinue ST permanently, most patients require prolonged ST. Viewing chronic GvHD in this way has implications for management approaches.

NCCN Guidelines® Insights: Hematopoietic Cell Transplantation, Version 3.2022.

The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease-a major complication of allogeneic HCT-to enable the patient and clinician to assess management options in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT.

Cannabinoid Receptor Type 1 regulates growth cone filopodia and axon dispersion in the optic tract of Xenopus laevis tadpoles.

Previous studies show that the main cannabinoid receptor in the brain-cannabinoid type 1 receptor (CB1R)-is required for establishment of axonal projections in developing neurons but questions remain regarding the cellular and molecular mechanisms, especially in neurons developing in their native environment. We assessed the effects of CB1R signalling on growth cone filopodia and axonal projections of retinal ganglion cells (RGCs) in whole mount brains from Xenopus laevis tadpoles. Our results indicate that growth cones of RGC axons in brains from tadpoles exposed to a CB1R agonist had fewer filopodial protrusions, whereas growth cones from tadpoles exposed to a CB1R inverse agonist had more filopodia than growth cones of RGC axons in whole brains from control tadpoles. However, application of both the CB1R agonist and inverse agonist resulted in RGC axons that were overly dispersed and undulatory in the optic tract in situ. In addition, expression of a mutant for cadherin adhesive factor, ß-catenin, that disrupts its binding to α-catenin, and application of an inhibitor for actin regulator non-muscle Myosin II, phenocopied the effects of the CB1R agonist and inverse agonist on growth cone filopodia, respectively. These findings suggest that both destablization and stabilization of growth cone filopodia are required for RGC axonal fasciculation/defasciculation in the optic tract and that CB1R regulates growth cone filopodia and axon dispersion of RGCs by oppositely modulating ß-catenin adhesive and Myosin II actin regulatory functions. This study extends and confirms our understanding of cannabinoid mechanisms in sculpting developing neuronal circuits in vivo.

The emerging role of transcription factor FOXP3 in thyroid cancer.

Transcription factor FOXP3 is a crucial regulator in the development and function of regulatory T cells (Treg) that are essential for immunological tolerance and homeostasis. Numerous studies have indicated the correlation of tumor infiltrating FOXP3+ Treg upregulation with poor prognostic parameters in thyroid cancer, including lymph node metastases, extrathyroidal extension, and multifocality. Most immune-checkpoint molecules are expressed in Treg. The blockage of such signals with checkpoint inhibitors has been approved for several solid tumors, but not yet for thyroid cancer. Thyroid abnormalities may be induced by checkpoint inhibitors. For example, hypothyroidism, thyrotoxicosis, painless thyroiditis, or even thyroid storm are more frequently associated with anti-PD-1 antibodies (pembrolizumab and nivolumab). Therefore, Targeting FOXP3+ Treg may have impacts on checkpoint molecules and the growth of thyroid cancer. Several factors may impact the role and stability of FOXP3, such as alternative RNA splicing, mutations, and post-translational modification. In addition, the role of FOXP3+ Treg in the tumor microenvironment is also affected by the complex regulatory network formed by FOXP3 and its transcriptional partners. Here we discussed how the expression and function of FOXP3 were regulated and how FOXP3 interacted with its targets in Treg, aiming to help the development of FOXP3 as a potential therapeutic target for thyroid cancer.

Methylation of ERß 5'-untranslated region attenuates its inhibitory effect on ERα gene transcription and promotes the initiation and progression of papillary thyroid cancer.

Normal thyroid tissue displays a prevalent expression of ERß than ERα, which drastically turns upside down in the initiation and progression of papillary thyroid cancer (PTC). The underlying molecular mechanism of this phenomenon remains unclear. Here, we demonstrated that ERα and ERß were coexpressed in human thyroid tissues and cells. ERα mRNA (A-1) and ERß mRNA (0N-1), transcribed from Promoter A of ERα gene and Promoter 0N of ERß gene, respectively, were the major mRNA isoforms which mainly contributed to total ERα mRNA and total ERß mRNA in human thyroid-derived cell lines and tissues. The expression levels of ERα mRNA (A-1) and total ERα mRNA were gradually increased, and those of ERß mRNA (0N-1) and total ERß mRNA were decreased by degree in the initiation and progression of PTC. No aberrant DNA methylation of ERα 5'-untranslated region was involved in its up-regulation; however, aberrant DNA methylation in Promoter 0N and Exon 0N of ERß gene was found to be involved in its down-regulation in the initiation and progression of PTC. ERß can repress ERα gene transcription via recruitment of NCoR and displacement of RNA polymerase II at the Sp1 site in ERα Promoter A-specific region in thyroid-derived cells. It is suggested that DNA methylation of CpG islands in Promoter 0N and Exon 0N of ERß gene leads to a decreased ERß gene expression, which attenuates its inhibitory effect on ERα gene transcription and results in an increased ERα gene expression, cell proliferation, initiation, and progression of PTC.

Screening of Endocrine Disrupting Potential of Surface Waters via an Affinity-Based Biosensor in a Rural Community in the Yellow River Basin, China.

Overcoming the limitations of traditional analytical methods and developing technologies to continuously monitor environments and produce a comprehensive picture of potential endocrine-disrupting chemicals (EDCs) has been an ongoing challenge. Herein, we developed a portable nuclear receptor (NR)-based biosensor within 90 min to perform highly sensitive analyses of a broad range of EDCs in environmental water samples. Based on the specific binding of the fluorescence-labeled NRs with their ligands, the receptors were attached to the EDC-functionalized fiber surface by competing with EDCs in the samples. The biosensor emitted fluorescence due to the evanescent wave excitation, thereby resulting in a turn-off sensing mode. The biosensor showed a detection limit of 5 ng/L E2-binding activity equivalent (E2-BAE) and 93 ng/L T3-BAE. As a case study, the biosensor was used to map the estrogenic binding activities of surface waters obtained from a rural community in the Yellow River basin in China. When the results obtained were compared with those from the traditional yeast two-hybrid bioassay, a high correlation was observed. It is anticipated that the good universality and versatility exhibited by this biosensor for various EDCs, which is achieved by using different NRs, will significantly promote the continuous assessment of global EDCs.

Oral-gut bacterial profiles discriminate between periodontal health and diseases.

OBJECTIVE: This investigation explored oral-gut microbial signatures with potential to distinguish among periodontal conditions. BACKGROUND DATA: The interplay between the oral and gut microbiomes may be a critical pathway linking periodontal diseases and systemic inflammatory disorders. The mechanisms by which oral microorganisms translocate to the gut and cause microbial dysbiosis, favoring an inflammatory state, are still unknown. As a first approach, characterization of oral-gut microbial profiles associated with periodontal health and diseases can provide insights on such mechanisms of etiology and pathogenesis. METHODS: Fecal and saliva samples from individuals with periodontal health (PH, 8), gingivitis (GG, 17), and periodontitis (PD, 24) were analyzed for their microbial composition by 16S rRNA gene sequencing. Microbial taxa were compared and correlated to periodontal parameters. Multivariate discriminant analysis (MDA) was carried out to identify profiles related to health and disease. RESULTS: Few significant differences in oral-gut taxa were detected among clinical groups, although increase in fecal Fusobacterium nucleatum ss vincentii and salivary Aggregatibacter actinomycetemcomitans, Parvimonas micra, and Fretibacterium sp. HMT358 were strongly correlated with deep pockets and inflammation (p < .01). Over 50% of the fecal microbiota comprised microorganisms shared between oral and gut sites, whereas oral taxa were detected in approximately 9%, particularly enriched in GG fecal samples (p = .04). Trends for lower fecal richness and higher salivary diversity in PD compared to PH were observed. MDA was able to classify correctly 82% of the patients into the clinical groups. Main classifiers of periodontitis were high BMI, older age, and enrichment of oral-fecal Leptotrichia sp. HMT4, Peptostreptococcus stomatis, Dialister invisus, and a novel Lautropia sp. HMTC89-like organism. CONCLUSION: Within the limitations of an exploratory investigation, specific profiles of oral-gut taxa, including known and potential novel organisms, combined with social-demographic features were able to discriminate individuals with periodontal diseases in this study population.

A comprehensive review on electrochemical and optical aptasensors for organophosphorus pesticides.

There has been a rise in pesticide use as a result of the growing industrialization of agriculture. Organophosphorus pesticides have been widely applied as agricultural and domestic pest control agents for nearly five decades, and they remain as health and environmental hazards in water supplies, vegetables, fruits, and processed foods causing serious foodborne illness. Thus, the rapid and reliable detection of these harmful organophosphorus toxins with excellent sensitivity and selectivity is of utmost importance. Aptasensors are biosensors based on aptamers, which exhibit exceptional recognition capability for a variety of targets. Aptasensors offer numerous advantages over conventional approaches, including increased sensitivity, selectivity, design flexibility, and cost-effectiveness. As a result, interest in developing aptasensors continues to expand. This paper discusses the historical and modern advancements of aptasensors through the use of nanotechnology to enhance the signal, resulting in high sensitivity and detection accuracy. More importantly, this review summarizes the principles and strategies underlying different organophosphorus aptasensors, including electrochemical, electrochemiluminescent, fluorescent, and colorimetric ones.

Targeting hepatocyte growth factor/c-mesenchymal-epithelial transition factor axis in hepatocellular carcinoma: Rationale and therapeutic strategies.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. The outcome of current standard treatments, as well as targeted therapies in advanced stages, are still unsatisfactory. Attention has been drawn to novel strategies for better treatment efficacy. Hepatocyte growth factor/c-mesenchymal-epithelial transition factor (HGF/c-Met) axis has been known as an essential element in the regulation of liver diseases and as an oncogenic factor in HCC. In this review, we collected the evidence of HGF/c-Met as a tumor progression and prognostic marker, discussed the anti-c-Met therapy in vitro, summarized the outcome of c-Met inhibitors in clinical trials, and identified potential impetus for future anti-c-Met treatments. We also analyzed the inconsistency of HGF/c-Met from various publications and offered reasonable explanations based on the current understanding in this area. In conclusion, HGF/c-Met plays a crucial role in the progression and growth of HCC, and the strategies to inhibit this pathway may facilitate the development of new and effective treatments for HCC patients.

The FKH domain in FOXP3 mRNA frequently contains mutations in hepatocellular carcinoma that influence the subcellular localization and functions of FOXP3.

The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.

Efficacy of bisphosphonates in detection of early enamel caries using NIR fluorescence imaging and inhibition of caries progression.

NIR fluorescence imaging using bisphosphonate-Indocyanine green has been indicated for early interproximal caries detection. This study assessed diagnostic accuracy of caries detection by NIR fluorescence imaging with OsteoSense 750® (OS750) in vitro and ex vivo, and to analyze the therapeutic efficacy of a bisphosphonate (Etidronate) in inhibiting enamel caries progression in vitro. Methods: Four experiments were conducted using extracted human teeth; 1) to calculate the infiltration rate of OS750 into interproximal white spot lesions using fluorescence microscope, 2) to assess diagnostic accuracy of interproximal natural white spot lesions using desktop NIR fluorescence imaging device in vitro setting, 3) to assess diagnostic accuracy of artificially created deeper enamel carious lesion (0.5 mm~1.0 mm) using NIR fluorescence image through the head-mount display in ex vivo setting, 4) to compare the progression on the enamel caries lesions treated by Etidronate, NaF and distilled-water. Diagnostic accuracy was analyzed using sensitivity, specificity and receiver operating curves (ROC). The caries progression was calculated with micro-CT and was statistically analyzed using a two-way ANOVA and the Tukey HDS post-hoc test. Results: 1) The infiltration rate of OS750 was 101.83% ± 8.66 (Min: 90.10%, Max: 133.94%). 2) The average of sensitivity and specificity in vitro setting experiments were 86.7% ± 4.4% and 70% ± 11%, respectively. The average of area under the ROC curves (AUC) was 0.883 ± 0.059 indicating excellent performance. 3) The mean sensitivity and specificity in ex vivo setting was 82.97% ± 15% and 76.78% ± 13.27% respectively. 4) The carious lesion volume treated by Etidronate was significantly smaller at post treatment-1 (p<0.05) and treatment-2 (p<0.01) than the control. There was no significant difference in lesion volume in the Etidronate and NaF group at the time point of post treatment-1. Conclusion: This study suggests that bisphosphonates contribute to both early diagnosis of enamel caries and inhibition of caries progression.

Review of Optical Humidity Sensors.

Optical humidity sensors have evolved through decades of research and development, constantly adapting to new demands and challenges. The continuous growth is supported by the emergence of a variety of optical fibers and functional materials, in addition to the adaptation of different sensing mechanisms and optical techniques. This review attempts to cover the majority of optical humidity sensors reported to date, highlight trends in design and performance, and discuss the challenges of different applications.

Carfilzomib for Treatment of Refractory Chronic Graft-versus-Host Disease: A Chronic GVHD Consortium Pilot Phase II Trial.

Previously reported experimental and clinical data suggest that proteasome inhibition may have immunomodulatory activity relevant to graft-versus-host disease (GVHD). To explore the safety and activity of carfilzomib in advanced chronic GVHD, we conducted a multicenter pilot phase II trial through the Chronic GVHD Consortium. Carfilzomib was administered at 20 mg/m2 on day 1, then 36 mg/m2 on days 8 and 15 of a 28-day treatment cycle (cycle 1), and then 36 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle (cycles 2 to 6). The primary endpoint was 6-month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic immunosuppressive therapy. A total of 20 subjects were enrolled at 4 institutions. The median time from chronic GVHD onset to enrollment was 1.5 years (interquartile range, 0.5 to 3.7 years). Chronic GVHD was National Institutes of Health category moderate (30%) or severe (70%), predominantly classic (90% versus overlap 10%), and involved multiple diverse organ sites. The number of previous lines of systemic therapy for chronic GVHD was ≤2 in 6 patients (30%) and ≥3 in the other 14 (70%). Doses were held primarily for infection (50% of total held doses); only 3 patients (15%) completed all planned doses of the 6 cycles of carfilzomib. Serious adverse effects occurred in 40% of the patients, and 7 patients died, between .3 and 9 months after the last carfilzomib dose, but no deaths were attributed to carfilzomib. The 6-month treatment failure rate was not significantly improved versus the historical benchmark rate (40% versus 44%; P = .36). Overall survival was 80% at 6 months and 65% at 12 months. Failure-free survival at 12 months was 32%. These pilot phase II data suggest that carfilzomib therapy in this advanced chronic GVHD population did not improve over the expected 6-month treatment failure rates achieved under conventional practices and is not recommended for further study for this indication.