Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and T cell proliferation.

Cytokine-mediated STAT5 protein activation is vital for lymphocyte development and function. In vitro tyrosine phosphorylation of a C-terminal tyrosine is critical for activation of STAT5A and STAT5B; however, the importance of STAT5 tyrosine phosphorylation in vivo has not been assessed. Here we generate Stat5a and Stat5b tyrosine-to-phenylalanine mutant knockin mice and find they have greatly reduced CD8+ T-cell numbers and profoundly diminished IL-2-induced proliferation of these cells, and this correlates with reduced induction of Myc, pRB, a range of cyclins and CDKs, and a partial G1→S phase-transition block. These mutant CD8+ T cells also exhibit decreased IL-2-mediated activation of pERK and pAKT, which we attribute in part to diminished expression of IL-2Rß and IL-2Rγ. Our findings thus demonstrate that tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling. Moreover, our transcriptomic and proteomic analyses elucidate the molecular basis of the IL-2-induced proliferation of CD8+ T cells.

LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling.

High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials. Herein, we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8+ T cells. Using IFN-γ production as a proxy for CD8+ T cell terminal differentiation, LMO4 emerged among the top hits inhibiting the development of effectors cells. Consistently, we found that Lmo4 was downregulated upon CD8+ T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells. By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8+ T cells, we enabled selective expansion and enhanced persistence of transduced cells, while limiting their terminal differentiation and senescence. LMO4 overexpression promoted transcriptional programs regulating stemness, increasing the numbers of stem-like CD8+ memory T cells and enhancing their polyfunctionality and recall capacity. When tested in syngeneic and xenograft tumor models, LMO4 overexpression boosted CD8+ T cell antitumor immunity, resulting in enhanced tumor regression. Rather than directly modulating gene transcription, LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21, inducing the expression of target genes (Tcf7, Socs3, Junb, and Zfp36) crucial for memory responses. CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4, thereby abrogating the therapeutic benefit of LMO4 overexpression. These results establish LMO4 overexpression as an effective strategy to boost CD8+ T cell stemness, providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

Engineered cytokine/antibody fusion proteins improve IL-2 delivery to pro-inflammatory cells and promote antitumor activity.

Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.

A novel integrated urban flood risk assessment approach based on one-two dimensional coupled hydrodynamic model and improved projection pursuit method.

Urban flood risk assessment is a complex task, as it requires extensive knowledge about hydrological features of the catchment, hydraulic characteristics of the drainage network and social characteristics of residential areas. How to accurately and efficiently quantify regional risk has always been a challenge in this field. To solve the problem, this study is developed to propose a novel integrated urban flood risk assessment approach based on one-two dimensional coupled hydrodynamic model and improved projection pursuit method. Two open source software like urban storm flood management model (SWMM) and TELEMAC-2D are introduced to build the one-two coupling hydrodynamic model through proprietary programming, which can accurately simulate urban inundation process. Based on the simulation results of hydrodynamic model and literature review, a set of urban flood risk assessment index system containing physical mechanism and statistical mechanism related index is established, including a total of 12 indicators covering three dimensions like hazard factor, exposure factor and vulnerability factor. Then an Improved Projection Pursuit (IPP) method coupling k-means clustering algorithm is proposed to determine the index weight. The novel integrated urban flood risk assessment approach is implemented in Suyu district, China. The results demonstrate that the accuracy and efficiency of evaluation urban flood risk assessment are greatly improved by the integrated approach. In conclusion, this research offers a novel methodology for urban flood risk assessment and contributes to decision-making in environmental management.

Safety of pembrolizumab as adjuvant therapy in a pooled analysis of phase 3 clinical trials of melanoma, non-small cell lung cancer, and renal cell carcinoma.

BACKGROUND: The safety profile of adjuvant pembrolizumab was evaluated in a pooled analysis of 4 phase 3 clinical trials. METHODS: Patients had completely resected stage IIIA, IIIB, or IIIC melanoma per American Joint Committee on Cancer, 7th edition, criteria (AJCC-7; KEYNOTE-054); stage IIB or IIC melanoma per AJCC-8 (KEYNOTE-716); stage IB, II, or IIIA non-small cell lung cancer per AJCC-7 (PEARLS/KEYNOTE-091); or postnephrectomy/metastasectomy clear cell renal cell carcinoma at increased risk of recurrence (KEYNOTE-564). Patients received adjuvant pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for approximately 1 year. Adverse events (AEs) were summarized for patients who received ≥ 1 dose of treatment. RESULTS: Data were pooled from 4125 patients treated with pembrolizumab (n = 2060) or placebo (n = 2065). Median (range) duration of treatment was 11.1 months (0.0-18.9) with pembrolizumab and 11.2 months (0.0-18.1) with placebo. Treatment-related AEs occurred in 78.6 % (1620/2060) of patients in the pembrolizumab group (grade 3-5, 16.3 % [336/2060]) and 58.7 % (1212/2065) in the placebo group (grade 3-5, 3.5 % [72/2065]). Immune-mediated AEs (e.g. adrenal insufficiency, hypophysitis, and thyroiditis) occurred in 36.2 % (746/2060) of patients in the pembrolizumab group (grade 3-5, 8.6 % [177/2060]) and 8.4 % (174/2065) in the placebo group (grade 3-5, 1.1 % [23/2065]). Of patients with ≥ 1 immune-mediated AE or infusion reaction, systemic corticosteroids were required for 35.2 % (268/761) and 20.2 % (39/193) of patients in the pembrolizumab and placebo groups, respectively. CONCLUSIONS: Adjuvant pembrolizumab demonstrated a manageable safety profile that was comparable to prior reports in advanced disease.

Identification and expression profiling of GAPDH family genes involved in response to Sclerotinia sclerotiorum infection and phytohormones in Brassica napus.

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a crucial enzyme in glycolysis, an essential metabolic pathway for carbohydrate metabolism across all living organisms. Recent research indicates that phosphorylating GAPDH exhibits various moonlighting functions, contributing to plant growth and development, autophagy, drought tolerance, salt tolerance, and bacterial/viral diseases resistance. However, in rapeseed (Brassica napus), the role of GAPDHs in plant immune responses to fungal pathogens remains unexplored. In this study, 28 genes encoding GAPDH proteins were revealed in B. napus and classified into three distinct subclasses based on their protein structural and phylogenetic relationships. Whole-genome duplication plays a major role in the evolution of BnaGAPDHs. Synteny analyses revealed orthologous relationships, identifying 23, 26, and 26 BnaGAPDH genes with counterparts in Arabidopsis, Brassica rapa, and Brassica oleracea, respectively. The promoter regions of 12 BnaGAPDHs uncovered a spectrum of responsive elements to biotic and abiotic stresses, indicating their crucial role in plant stress resistance. Transcriptome analysis characterized the expression profiles of different BnaGAPDH genes during Sclerotinia sclerotiorum infection and hormonal treatment. Notably, BnaGAPDH17, BnaGAPDH20, BnaGAPDH21, and BnaGAPDH22 exhibited sensitivity to S. sclerotiorum infection, oxalic acid, hormone signals. Intriguingly, under standard physiological conditions, BnaGAPDH17, BnaGAPDH20, and BnaGAPDH22 are primarily localized in the cytoplasm and plasma membrane, with BnaGAPDH21 also detectable in the nucleus. Furthermore, the nuclear translocation of BnaGAPDH20 was observed under H2O2 treatment and S. sclerotiorum infection. These findings might provide a theoretical foundation for elucidating the functions of phosphorylating GAPDH.

Rejuvenating fecal microbiota transplant enhances peripheral nerve repair in aged mice by modulating endoneurial inflammation.

Peripheral nerve injury (PNI) resulting from trauma or neuropathies can cause significant disability, and its prognosis deteriorates with age. Emerging evidence suggests that gut dysbiosis and reduced fecal short-chain fatty acids (SCFAs) contribute to an age-related systemic hyperinflammation (inflammaging), which hinders nerve recovery after injury. This study thus aimed to evaluate the pro-regenerative effects of a rejuvenating fecal microbiota transplant (FMT) in a preclinical PNI model using aged mice. Aged C57BL/6 mice underwent bilateral crush injuries to their sciatic nerves. Subsequently, they either received FMT from young donors at three and four days after the injury or retained their aged gut microbiota. We analyzed gut microbiome composition and SCFA concentrations in fecal samples. The integrity of the ileac mucosal barrier was assessed by immunofluorescence staining of Claudin-1. Flow cytometry was utilized to examine immune cells and cytokine production in the ileum, spleen, and sciatic nerve. Various assessments, including behavioural tests, electrophysiological studies, and morphometrical analyses, were conducted to evaluate peripheral nerve function and repair following injury. Rejuvenating FMT reversed age-related gut dysbiosis by increasing Actinobacteria, especially Bifidobacteriales genera. This intervention also led to an elevation of gut SCFA levels and mitigated age-related ileac mucosal leakiness in aged recipients. Additionally, it augmented the number of T-helper 2 (Th2) and regulatory T (Treg) cells in the ileum and spleen, with the majority being positive for anti-inflammatory interleukin-10 (IL-10). In sciatic nerves, rejuvenating FMT resulted in increased M2 macrophage counts and a higher IL-10 production by IL-10+TNF-α- M2 macrophage subsets. Ultimately, restoring a youthful gut microbiome in aged mice led to improved nerve repair and enhanced functional recovery after PNI. Considering that FMT is already a clinically available technique, exploring novel translational strategies targeting the gut microbiome to enhance nerve repair in the elderly seems promising and warrants further evaluation.

Boosting N2 Conversion into NH3 over Ru Catalysts via Modulating the Ru-Promoter Interface.

Promoters are indispensable components of Ru-based catalysts to promote N2 activation in ammonia (NH3) synthesis. The rational addition and regulation of promoters play a critical role in affecting the NH3 synthesis rate. In this work, we report a simple method by altering the loading sequence of Ba and Ru species to modulate the Ru-promoter interface, thus significantly boosting the NH3 synthesis rate. The Ba-Ru/GC BM catalyst via the prior loading of Ba rather than Ru over graphitic carbon (GC) exhibits a high NH3 synthesis rate of 18.7 mmol gcat-1 h-1 at 400 °C and 1 MPa, which is 2.5 times that of the Ru-Ba/GC BM catalyst via the conventional prior loading of Ru rather than Ba on GC. Our studies reveal that the prior loading of Ba benefits the high dispersion of the basic Ba promoter over an electron-withdrawing GC support, and then Ba species serve as structural promoters to stabilize Ru with small particle sizes, which exposes more active sites for N2 activation. Additionally, the intimate Ba and Ru interface enables facile electron donation from Ba to Ru sites, thus accelerating N2 dissociation to realize efficient NH3 synthesis. This work provides a simple approach to modulating the Ru-promoter interface and maximizing promoter utilization to enhance NH3 synthesis performance.

Distinct use of super-enhancer elements controls cell type-specific CD25 transcription and function.

The IL-2 receptor α chain (IL-2Rα/CD25) is constitutively expressed on double-negative (DN2/DN3 thymocytes and regulatory T cells (Tregs) but induced by IL-2 on T and natural killer (NK) cells, with Il2ra expression regulated by a STAT5-dependent super-enhancer. We investigated CD25 regulation and function using a series of mice with deletions spanning STAT5-binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and Tregs, with these mice developing autoimmune alopecia, whereas deleting an intronic region decreased IL-2-induced CD25 on peripheral T and NK cells. Thus, distinct super-enhancer elements preferentially control constitutive versus inducible expression in a cell type-specific manner. The mediator-1 coactivator colocalized with specific STAT5-binding sites. Moreover, both upstream and intronic regions had extensive chromatin interactions, and deletion of either region altered the super-enhancer structure in mature T cells. These results demonstrate differential functions for distinct super-enhancer elements, thereby indicating previously unknown ways to manipulate CD25 expression in a cell type-specific fashion.

The Influence of the Genotype and Planting Density on the Structure and Composition of Root and Rhizosphere Microbial Communities in Maize.

Maize has the largest cultivation area of any crop in the world and plays an important role in ensuring food security. High-density planting is essential for maintaining high maize yields in modern intensive agriculture. Nonetheless, how high-density planting and the tolerance of individual genotypes to such planting shape the root-associated microbiome of maize is still unknown. In this study, we analyzed the root and rhizosphere bacterial communities of two maize accessions with contrasting shoot architectures grown under high- and low-density planting conditions. Our results suggested that maize hosted specific, distinct bacterial communities in the root endocompartment and that the maize genotype had a significant effect on the selection of specific microbes from the rhizosphere. High-density planting also had significant effects on root-associated bacterial communities. Specifically, genotype and high-density planting coordinated to shape the structure, composition, and function of root and rhizosphere bacterial communities. Taken together, our results provide insights into how aboveground plant architecture and density may alter the belowground bacterial community in root-associated compartments of maize.

Long-term golimumab persistence: Five-year treatment retention data pooled from pivotal Phase III clinical trials in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

INTRODUCTION: Golimumab, a monoclonal antibody against tumor necrosis factor-α (TNF-α), is used widely for treatment of rheumatic diseases. Long-term persistence is an important factor influencing therapeutic benefit and is a surrogate measure of efficacy. We compared five-year golimumab treatment persistence across studies, indications, and lines of therapy using pooled data from pivotal golimumab Phase III clinical trials. METHODS: This post-hoc analysis evaluated use of golimumab administered subcutaneously (50 or 100 mg every four weeks) for up to five years in 2228 adult participants with rheumatoid arthritis (RA; GO-BEFORE, GO-AFTER, and GO-FORWARD studies), psoriatic arthritis (PsA; GO-REVEAL study), or ankylosing spondylitis (AS; GO-RAISE study). Retention rate differences were evaluated by study, indication, and line of therapy using log-rank tests, and probability of treatment persistence was estimated by Kaplan-Meier analysis. RESULTS: Golimumab retention rates at Year 5 were consistently high when used as 1st-line therapy (69.8%) and did not differ significantly across the three indications tested (p = 0.5106) or across 1st-line studies (p = 0.2327). Retention at Year 5 was better in participants using golimumab as 1st-line than in those using it as 2nd-line (41.6%) therapy. Participants on 2nd-line golimumab therapy had a longer disease duration (median 9.2 years versus 3.7 years) than those on 1st-line golimumab therapy. CONCLUSIONS: These data support the value of long-term golimumab therapy in patients with chronic, immune-mediated rheumatic diseases when used as 1st-line (RA, PsA, AS) or 2nd-line (RA) therapy. Key Points • Golimumab is a human monoclonal antibody directed against tumor necrosis factor-α (TNF-α) and is approved widely for the treatment of rheumatic autoimmune diseases. • We compared the probability of treatment persistence, or the time of continuous drug use, for golimumab across five Phase III studies spanning multiple rheumatic indications over five years. • Treatment persistence was favorable and did not differ significantly for participants with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, but persistence was greater when golimumab was used as 1st-line than as 2nd-line biologic therapy.

Low Occurrence of Colectomy With Long-Term (up to 4 Years) Golimumab Treatment in Patients With Moderate-to-Severe Active Ulcerative Colitis: Data From the PURSUIT Maintenance and Long-Term Extension Studies.

Background: This analysis evaluated the incidence of all-cause colectomies (total or partial) among patients with moderate-to-severe active ulcerative colitis (UC) in the golimumab (GLM) Program of Ulcerative Colitis Utilizing an Investigational Treatment (PURSUIT)-maintenance (-M) and long-term extension (-LTE) studies. Methods: Eligible PURSUIT-M trial participants completed a 6-week GLM induction trial without requiring colectomy. Responders to GLM induction were randomized 1:1:1 to GLM 50 mg, GLM 100 mg, or placebo (PBO) maintenance for up to 1 year, administered every 4 weeks (q4w). Nonresponders to GLM or PBO induction received GLM 100 mg; responders to PBO induction received PBO (each administered q4w for up to 1 year). Participants who completed PURSUIT-M were eligible to continue their treatment in the 3-year PURSUIT-LTE study. Results: A total of 60 (4.9%) colectomies were reported among the 1228 patients who enrolled in the 1-year PURSUIT-M study, which included 672 participants who continued into the 3-year PURSUIT-LTE LTE study (of which 666 were treated). The colectomy rate during the 3-year extension was lower than that observed during the maintenance phase of the study (9/666 [1.4%] compared to 51/1228 [4.2%]). The majority (43/60 [71.7%]) of the reported colectomies occurred in patients who had not responded to induction therapy and who tended to have had more severe disease characteristics at baseline. Conclusions: This retrospective evaluation of colectomy data from the PURSUIT-M and -LTE studies in patients with moderate-to-severe active UC demonstrated a low (<5%) occurrence of colectomy with long-term (up to 4 years) GLM treatment. PURSUIT-M (NCT00488631; EudraCT, 2006-003399-37).

Boosting the ammonia synthesis activity of ceria-supported Ru catalysts achieved through trace Pr addition.

The amount of dopant used in conventional cases for improving catalytic performance is higher than 5%. In this work, a strategy to enhance the ammonia synthesis performance of a Ru/CeO2 catalyst by using trace Pr (0.1 mol%) is reported. Owing to the improvement of oxygen defects, Ce3+ concentration and interfaced Ru species, the hydrogen adsorption was enhanced, and the desorption of hydrogen species would be promoted. As a result, Ru/CeO2 with 0.1 mol% Pr shows 1.4 times higher ammonia synthesis rate and excellent stability compared to Ru/CeO2 or the sample with high Pr loading (50 mol% Pr). This study provides a new idea for the design of high-efficiency ammonia synthesis catalysts.

Equivalence between radial quadrature and finite series for spherical wave expansion of Bessel beams.

The radial quadrature method was recently proposed for formulating the beam shape coefficients (BSCs) for shaped beams. A new deduction of BSCs using the R-quadrature method is presented in this paper, using the integral of the spherical Bessel functions in the interval ranging from zero to infinity. Based on the scalar description of the Bessel beam, the equivalence between the R-quadrature and the finite series (FS) method is confirmed. The spherical wave expansion of the scalar function allows us to simplify the formulation of the BSCs in the R-quadrature and the FS and to speed up the numerical BSC calculation. As a by-product, FS expansions of the associated Legendre functions are established, which we do not find in the literature.

Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial.

BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL-1·beat-1), PA compliance (0.58 mL·mmHg-1), cardiac efficiency (0.48 mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39 cm2 and -5.31 cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.

Strategies to therapeutically modulate cytokine action.

Cytokines are secreted or membrane-presented molecules that mediate broad cellular functions, including development, differentiation, growth and survival. Accordingly, the regulation of cytokine activity is extraordinarily important both physiologically and pathologically. Cytokine and/or cytokine receptor engineering is being widely investigated to safely and effectively modulate cytokine activity for therapeutic benefit. IL-2 in particular has been extensively engineered, to create IL-2 variants that differentially exhibit activities on regulatory T cells to potentially treat autoimmune disease versus effector T cells to augment antitumour effects. Additionally, engineering approaches are being applied to many other cytokines such as IL-10, interferons and IL-1 family cytokines, given their immunosuppressive and/or antiviral and anticancer effects. In modulating the actions of cytokines, the strategies used have been broad, including altering affinities of cytokines for their receptors, prolonging cytokine half-lives in vivo and fine-tuning cytokine actions. The field is rapidly expanding, with extensive efforts to create improved therapeutics for a range of diseases.

Constrained Maximum Cross-Domain Likelihood for Domain Generalization.

As a recent noticeable topic, domain generalization aims to learn a generalizable model on multiple source domains, which is expected to perform well on unseen test domains. Great efforts have been made to learn domain-invariant features by aligning distributions across domains. However, existing works are often designed based on some relaxed conditions which are generally hard to satisfy and fail to realize the desired joint distribution alignment. In this article, we propose a novel domain generalization method, which originates from an intuitive idea that a domain-invariant classifier can be learned by minimizing the Kullback-Leibler (KL)-divergence between posterior distributions from different domains. To enhance the generalizability of the learned classifier, we formalize the optimization objective as an expectation computed on the ground-truth marginal distribution. Nevertheless, it also presents two obvious deficiencies, one of which is the side-effect of entropy increase in KL-divergence and the other is the unavailability of ground-truth marginal distributions. For the former, we introduce a term named maximum in-domain likelihood to maintain the discrimination of the learned domain-invariant representation space. For the latter, we approximate the ground-truth marginal distribution with source domains under a reasonable convex hull assumption. Finally, a constrained maximum cross-domain likelihood (CMCL) optimization problem is deduced, by solving which the joint distributions are naturally aligned. An alternating optimization strategy is carefully designed to approximately solve this optimization problem. Extensive experiments on four standard benchmark datasets, i.e., Digits-DG, PACS, Office-Home, and miniDomainNet, highlight the superior performance of our method.

Pembrolizumab plus chemotherapy for advanced non-small-cell lung cancer without tumor PD-L1 expression in Asia.

Aim: We pooled patient-level data from three randomized controlled studies to evaluate the combination of pembrolizumab plus chemotherapy in patients with untreated advanced/metastatic non-small-cell lung cancer (NSCLC) and programmed cell death ligand 1 (PD-L1) tumor proportion score <1% in East Asia. Methods: The analysis included 107 patients from China, Japan, Korea, Thailand and Taiwan (pembrolizumab plus chemotherapy, n = 56; chemotherapy alone, n = 51). Results: For pembrolizumab plus chemotherapy versus chemotherapy alone, median overall survival was 21.3 versus 12.6 months (HR, 0.55 [95% CI: 0.35-0.87]) and median progression-free survival was 8.4 versus 6.0 months (HR, 0.64 [95% CI: 0.43-0.96]). Conclusion: The analysis supports the use of pembrolizumab in combination with platinum-based chemotherapy for East Asian patients with PD-L1-negative, advanced NSCLC.

This analysis evaluated outcomes for East Asian patients with a type of advanced lung cancer which does not express a protein called programmed cell death ligand 1 (PD-L1). The patients received either an immunotherapy, called pembrolizumab, in combination with chemotherapy or chemotherapy alone. Overall survival (how long people live) and progression-free survival (how long people live without their disease getting worse) were longer for patients who received treatment with pembrolizumab plus chemotherapy versus those who received chemotherapy alone. Side effects among East Asian patients were similar to those previously described for a global patient population. These results support the use of pembrolizumab in combination with chemotherapy for East Asian patients with lung cancer that does not express PD-L1. Clinical Trial Registration: NCT02039674; NCT02578680; NCT03950674; NCT02775435; NCT03875092 (ClinicalTrials.gov).

Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy for relapsed/refractory classical Hodgkin lymphoma.

Previous analyses of the phase 2 KEYNOTE-087 (NCT02453594) trial of pembrolizumab monotherapy demonstrated effective antitumor activity with acceptable safety in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). However, long-term response durability and outcome of patients who receive a second course after treatment discontinuation after complete response (CR) remain of clinical interest. We present KEYNOTE-087 data after >5 years of median follow-up. Patients with R/R cHL and progressive disease (PD) after autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV; cohort 1), salvage chemotherapy and BV without ASCT (cohort 2), or ASCT without subsequent BV (cohort 3), received pembrolizumab for ≤2 years. Patients in CR who discontinued treatment and subsequently experienced PD were eligible for second-course pembrolizumab. Primary end points were the objective response rate (ORR) using blinded central review and safety. The median follow-up was 63.7 months. ORR was 71.4% (95% confidence interval [CI], 64.8-77.4; CR, 27.6%; partial response, 43.8%). Median duration of response (DOR) was 16.6 months; median progression-free survival was 13.7 months. A quarter of responders, including half of complete responders, maintained a response for ≥4 years. Median overall survival was not achieved. Among 20 patients receiving second-course pembrolizumab, ORR for 19 evaluable patients was 73.7% (95% CI, 48.8-90.8); median DOR was 15.2 months. Any-grade treatment-related adverse events occurred in 72.9% of patients and grade 3 or 4 adverse events occurred in 12.9% of patients; no treatment-related deaths occurred. Single-agent pembrolizumab can induce durable responses, particularly in patients achieving CR. Second-course pembrolizumab frequently reinduced sustained responses after relapse from initial CR.