Long-term Response Research Articles

Primary resistance to nivolumab plus ipilimumab therapy affects second-line treatment outcomes in patients with metastatic renal cell carcinoma.

Nivolumab plus ipilimumab (NIVO+IPI) has a long-term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second-line treatment in patients with mRCC. The data used in this multi-institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Associations between PRD and progression-free survival of second-line treatment (PFS), progression-free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male-dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176-2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649-6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040-5.437; p < 0.001). Before starting second-line therapy, patients with PRD tended to have a poor performance status compared with non-PRD patients and a higher IMDC risk. Second-line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first-line treatment was associated with poor clinical course, even with second-line therapy.

Three modes of viral adaption by the heart.

Viruses elicit long-term adaptive responses in the tissues they infect. Understanding viral adaptions in humans is difficult in organs such as the heart, where primary infected material is not routinely collected. In search of asymptomatic infections with accompanying host adaptions, we mined for cardio-pathogenic viruses in the unaligned reads of nearly 1000 human hearts profiled by RNA sequencing. Among virus-positive cases (~20%), we identified three robust adaptions in the host transcriptome related to inflammatory nuclear factor κB (NF-κB) signaling and posttranscriptional regulation by the p38-MK2 pathway. The adaptions are not determined by the infecting virus, and they recur in infections of human or animal hearts and cultured cardiomyocytes. Adaptions switch states when NF-κB or p38-MK2 is perturbed in cells engineered for chronic infection by the cardio-pathogenic virus, coxsackievirus B3. Stratifying viral responses into reversible adaptions adds a targetable systems-level simplification for infections of the heart and perhaps other organs.

Abstract B050: Frequent monitoring of NSCLC immunotherapy using an mDETECT liquid biopsy reveals unexpected complexity and opportunities

Abstract We have developed a version of our "methylation DETection of Circulating Tumour" DNA (mDETECT) assay that is able to sensitively and quantitatively monitor Non-Small Cell Lung Cancer (NSCLC). We used this assay to frequently assess the tumour burden of a small cohort (17 individuals) of patients undergoing first line monotherapy with pembrolizumab for metastatic disease. Patients were tested weekly or biweekly in the period immediately after initiation of treatment with radiological assessment being done at approximately 3 months. Radiologically non-responding patients showed constant or increased mDETECT levels over the 3 month time frame. Responding patients showed 2 different patterns, with some showing dramatically increasing mDETECT levels for a short period of time followed by a rapid decrease. Other responders showed an immediate decrease within the first few week of treatment. In both responder groups these decreases were associated with a longer term response. Continued monitoring did reveal eventual progression in some of these patients with increasing mDETECT levels being seen 4 to 6 months before radiological changes. In some non-responding patients complex responses were seen, with mDETECT levels varying significantly over time. In one non-responding patient the addition of carboplatin to their treatment regime did produce a temporary improvement in their mDETECT levels. Frequent assessment of tumour burden by a liquid biopsy such as mDETECT offers the opportunity to rapidly determine a patient's response to therapy and potentially modify treatments to improve responses. Citation Format: Christopher R Mueller, Keira Parr, Mihaela Mates, Andrew Robinson, Harriet Feilotter, Keira Frosst. Frequent monitoring of NSCLC immunotherapy using an mDETECT liquid biopsy reveals unexpected complexity and opportunities [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B050.

Learning extreme vegetation response to climate drivers with recurrent neural networks

Abstract. The spectral signatures of vegetation are indicative of ecosystem states and health. Spectral indices used to monitor vegetation are characterized by long-term trends, seasonal fluctuations, and responses to weather anomalies. This study investigates the potential of neural networks in learning and predicting vegetation response, including extreme behavior from meteorological data. While machine learning methods, particularly neural networks, have significantly advanced in modeling nonlinear dynamics, it has become standard practice to approach the problem using recurrent architectures capable of capturing nonlinear effects and accommodating both long- and short-term memory. We compare four recurrent-based learning models, which differ in their training and architecture for predicting spectral indices at different forest sites in Europe: (1) recurrent neural networks (RNNs), (2) long short-term memory networks (LSTMs), (3) gated recurrent unit networks (GRUs), and (4) echo state networks (ESNs). While our results show minimal quantitative differences in their performances, ESNs exhibit slightly superior results across various metrics. Overall, we show that recurrent network architectures prove generally suitable for vegetation state prediction yet exhibit limitations under extreme conditions. This study highlights the potential of recurrent network architectures for vegetation state prediction, emphasizing the need for further research to address limitations in modeling extreme conditions within ecosystem dynamics.

Response to rhGH therapy in short children born at very low birth weight.

Although the clinical benefits of long-term rhGH therapy have been well demonstrated in children born small for gestational age (SGA), little is known about the outcomes of this therapy in children born with very low birth weight (VLBW). This study aimed to report the short and long-term response to rhGH therapy in a cohort of VLBW patients, comparing subgroups according to size, gestational age, and causal factors associated with VLBW. We describe 33 patients born at VLBW treated with rhGH; 16 also received GnRHa. Medical records were analyzed at baseline and after one year of rhGH treatment. Data on the adult height SDS from 23 patients were also collected. Growth velocities and height SDS changes were calculated, along with the differences between the observed and predicted growth velocities. The first-year growth velocity (7.5±2.1cm/y) was aligned with prediction models for SGA children. After one year of rhGH treatment, height SDS improved from -3.0±1.1 to -2.6±1.3, with no differences among subgroups. Among patients reaching adult height, 73.9% remained short (-2.5±1.3) after long-term therapy (6.7±3.3y). The initial height SDS, height SDS change in the first year of treatment, and target height SDS were key independent predictors of height gain. The response to rhGH treatment was suboptimal in the VLBW group, independent of the size, gestational age, or etiological diagnosis. However, adult height may be improved in patients receiving rhGH treatment. This underscores the need for tailored protocols and further investigations to optimize outcomes in this population.

Long-Term Physiological Adaptations Induced by Short-Interval High-Intensity Exercises: An RCT Comparing Active and Passive Recovery

Background: High-intensity interval training (HIIT) is one of the most debated methods involving several parameters that could be modulated, but the long-term adaptations it induces are still unclear. This investigation aimed to evaluate the efficacy of running and whole-body exercises with high-intensity (&gt;80% heart rate) short intervals (30 s) in body composition and physical performance and compare the effects between groups with active (AR) or passive recovery (PR), both in males and females. Methods: Eighteen trained young adults (55.56% ♀) were randomly allocated to the PR (n = 9, 23.09 ± 2.56 years, 163.69 ± 9.88 cm, 68.96 ± 14.62 kg) or AR (n = 9, 22.05 ± 1.54 years, 170.61 ± 11.5 cm, 68.78 ± 12.45 kg) group. Both groups performed eight weeks of HIIT, with an equal progression, training, and volume load (TL: F = 1.55, p = 0.214; VL: F = 0.81, p = 0.505). Body fat (BF), fat-free mass (FFM), upper and lower limb fat (UFI, LFI) and muscle areas (UMA, LMA), handgrip strength (HGS), power (countermovement jump, CMJ), agility (5-0-5), and maximal oxygen consumption (V˙O2p) were tested before and after treatments. Results: The proposed HIIT reduced BF by 9.57% and increased FFM by 2.09%. Females reported better adaptations in LMA (8.34 times higher than males), while both sexes’ upper limb mass distribution was better affected by PR (♀: UFI g = 1.851, 95% CI: 0.51, 3.14; ♂: UFI g = 2.456, 95% CI: 0.336, 4.487). Concerning conditioning, the protocol increased V˙O2p by 6.47%. Females showed better adaptations in CMJ (RR = 1.8), while males showed better adaptations in agility (RR = 3.76). The interaction effects were significant for PR females (right = +6.28%; left = +9.28%) and for AR males (right = +19.21%; left = +19.04%) in HGS. Conclusions: Short-interval HIIT with different exercise recovery types may be a practical solution in training where several physiological improvements are needed. Coaches and trainers can take advantage of the versatile nature of HIIT, relying on desired movement patterns and long-term responses in both male and female individuals.

Investigating bacteria-induced inflammatory responses using novel endometrial epithelial gland organoid models

IntroductionThe endometrium plays a crucial role in early human pregnancy, particularly in embryo implantation, survival, and growth. However, invasion and infection by pathogens can lead to endometritis, infertility, and poor reproductive outcomes. Understanding the mechanisms of endometritis and its impact on fertility remains limited. An infection model using patient-derived endometrial epithelial gland organoids (EEGOs) was established to advance in vitro studies on endometritis and related infertility.MethodsAn EEGOs infection model was constructed and characterized from human endometrium, treating the organoids with estrogen and progesterone to observe changes in the proliferative and secretory phases. The organoids were infected with E. coli, and the release of inflammatory cytokines in the supernatant was detected using ELISA. RNA-seq was employed to analyze the differences before and after E. coli treatment, and differential gene mRNA expression was validated using real-time quantitative PCR. Additionally, the effect of E2 in alleviating inflammation was assessed through markers of receptivity (PAEP, LIF, ITGβ), proliferation (Ki67), and barrier repair (ZO-1).ResultsThe constructed human EEGOs exhibited long-term expansion capability, genetic stability, and characteristic hormonal responses, strongly expressing epithelial markers (MUC1, E-Cadherin). After E. coli infection, the expression levels of inflammatory cytokines TNF-α, IL-8, and IFN-γ increased significantly (P &amp;lt; 0.05). RNA-seq indicated that the MAPK signaling pathway was activated post-infection, with increased expression levels of heat shock proteins and transcription factor mRNA. E2 treatment post-infection significantly decreased the mRNA expression of inflammatory genes IL-1β, IL8, IL6 and TNF-α compared to the E. coli infected group (P &amp;lt; 0.05). Additionally, the expression of genes related to receptivity, proliferation, and barrier repair was enhanced in the E2-treated organoids.ConclusionsOur findings demonstrate that patient-derived EEGOs are responsive to bacterial infection and are effective models for studying host-pathogen interactions in bacterial infections. These organoids revealed the anti-inflammatory potential of E2 in alleviating E. coli-induced inflammation, providing insights into the mechanisms of endometritis and its impact on infertility. The study supports the use of EEGOs as valuable tools for understanding endometrial health and developing targeted treatments.

Abstract 4137246: Atrial Fibrillation Wave Vectors Determined by Artificial-Intelligence Indicate Clinical Phenotypes

Background: Atrial fibrillation (AF) is a major cause of morbidity and mortality, which may be reduced by ablation. However, it is difficult to predict patients who will respond, which is currently done using bedside variables since even experts find it difficult to interpret electrical signals (electrograms) or maps in AF, or link them with phenotype, acute or long-term ablation response. Hypothesis: We hypothesized that determining if AF waves consistently propagate away from the pulmonary veins (PV), identified using artificial-intelligence (AI) tools applied to spatial grids in multipolar catheters, may reflect phenotypes of response to ablation or other clinical features. Methods: We studied 26,640 electrograms in N=37 patients at AF ablation ( 66.3 ± 8.6 years, 13.5% women, 59.5% non-paroxysmal AF). We trained AI-algorithms to identify activation patterns and calculate propagation vectors in AF. Each patient had AF recordings from 64-pole basket catheters, from which we calculated AI-based vectors in 48 spatial grids of 3X3 electrodes (covering ~1-3 cm 2 ) over 1 minute (720 per patient). Fig. A illustrates AF waves predominantly exiting the PVs in a 60 year old man. We studied wave maps exiting the PVs in relation to AF type, termination of AF during ablation and 1 year outcome. Results: Ablation success for the cohort was 71.4% at 1 year. Wave direction in AF shifted over time, as expected, but predominant vectors correlated with clinical outcomes. Fig. B showed that AF waves were significantly more likely to exit the PVs for patients with success than failed ablation (&lt;0.05). Fig. C showed that PV wave direction did not differ for AF type, nor for patients with or without acute AF termination by ablation (p=NS). Conclusions: In this study of patients with various types of AF, a novel AI-based approach showed that AF vectors indicating waves exiting the PVs predicted , clinical phenotypes, particularly patients with successful ablation targeting the PVs.

A novel probabilistic analysis method for long-term dynamical response analysis

A novel probabilistic analysis method for long-term dynamical response analysis

EXTH-40. IMMUNOPHENOTYPING OF RWTC-MBTA AUTOLOGOUS CANCER VACCINE IN PRECLINICAL GLIOBLASTOMA MODELS

Abstract Despite advances in immunotherapy, glioblastoma multiforme (GBM) remains challenging to treat due to its low inherent immunogenicity and a suppressive tumor microenvironment. Converting “cold” GBMs to “hot” tumors is crucial for effective immune activation and improved patient outcomes. We comprehensively characterized the rWTC-MBTA autologous cancer vaccine, consisting of Mannan-BAM-anchored irradiated whole tumor cells, Toll-like receptor ligands (LTA, Poly(I:C), R-848), and an anti-CD40 agonistic antibody, in preclinical GL261 and SB28 GBM models. A substantial number of vaccinated mice exhibited complete regression of GBM tumors in a T-cell-dependent manner, with no significant toxicity. Long-term tumor-specific immune memory was confirmed upon tumor rechallenge. In the vaccine-draining lymph nodes of the SB28 model, rWTC-MBTA vaccination triggered a major rise in cDC1 12 hours post-treatment, followed by an increase in cDC2, moDC, and pDC on Days 5 and 13. Enhanced cytotoxicity of CD4+ and CD8+ T cells in vaccinated mice was verified in co-culture with tumor cells. Comprehensive immunophenotyping in the GL261 and SB28 GBM microenvironments confirmed decreased regulatory T cells and increased CD4+ and CD8+ T cell infiltration in vaccinated mice. T-cell exhaustion analyses revealed an increase in the Tim3+CD8+ T cells. No significant differences were observed in the quantification of M-MDSC and PMN-MDSC between control and vaccinated mice, but PD-L1 expression significantly increased in M2 macrophages in vaccinated mice. Our findings demonstrate that rWTC-MBTA induces potent and long-term adaptive immune responses against GBM, warranting further investigation of combinations with other immunotherapies for enhanced efficacy.

Oral Administration of Zinc Sulfate with Intramuscular Foot-and-Mouth Disease Vaccine Enhances Mucosal and Systemic Immunity

Background/Objectives: Foot-and-mouth disease (FMD) remains a significant global threat to livestock farming. Current commercial FMD vaccines present several challenges, including the risk of infection and adverse injection site reactions due to oil-based adjuvants. The complex immune environment of the gut-associated lymphoid tissue has the potential to induce broad and diverse immune responses. Therefore, we aimed to explore the potential of zinc sulfate as an oral adjuvant to enhance intestinal mucosal immunity and complement the effects of intramuscular (IM) FMD vaccination. Methods: We conducted serological analyses on mice and pigs, measuring secretory IgA (sIgA) levels and evaluating the expression of mucosal immunity-related genes in pigs. These assessments were used to investigate the systemic and mucosal immune responses induced by oral zinc sulfate administration in combination with an IM FMD vaccine. Results: This combination strategy significantly increased structural protein antibody titers and virus neutralization titers in experimental animals (mice) and target animals (pigs) across early, mid-, and long-term periods. Additionally, this approach enhanced the expression of key cytokines associated with mucosal immunity and increased sIgA levels, which are critical markers of mucosal immunity. Conclusions: Oral zinc sulfate administration may synergize with inactivated FMD vaccines, leading to sustained and enhanced long-term immune responses. This novel strategy could reduce the frequency of required vaccinations or allow for a lower antigen dose in vaccines, effectively stimulating the mucosal immune system and boosting systemic immunity. This approach has the potential to improve the overall efficacy of commercial FMD vaccines.

Interactions Between Bovine Respiratory Syncytial Virus and Cattle: Aspects of Pathogenesis and Immunity

Bovine respiratory syncytial virus (BRSV) is a major respiratory pathogen in cattle and is relevant to the livestock industry worldwide. BRSV is most severe in young calves and is often associated with stressful management events. The disease is responsible for economic losses due to lower productivity, morbidity, mortality, and prevention and treatment costs. As members of the same genus, bovine and human RSV share a high degree of homology and are similar in terms of their genomes, transmission, clinical signs, and epidemiology. This overlap presents an opportunity for One Health approaches and translational studies, with dual benefits; however, there is still a relative lack of studies focused on BRSV, and the continued search for improved prophylaxis highlights the need for a deeper understanding of its immunological features. BRSV employs different host-immunity-escaping mechanisms that interfere with effective long-term memory responses to current vaccines and natural infections. This review presents an updated description of BRSV’s immunity processes, such as the PRRs and signaling pathways involved in BRSV infection, aspects of its pathogeny, and the evading mechanisms developed by the virus to thwart the immune response.

Soil-Dwelling Arthropods’ Response to Land Abandonment Is Taxon-Specific in a Mediterranean Olive Grove Agroecosystem

Agricultural land abandonment is an increasing concern in the EU, especially in Mediterranean regions where traditional perennial crops like olive groves are left unmanaged. This study focuses on the impact of land abandonment on soil-dwelling arthropods in olive groves in Monte Pisano, Tuscany, examining ants, spiders, myriapods, and carabids. Using Generalized Linear Mixed Models, the potential olive fruit fly predator community was analyzed over two sampling periods repeated over two years to assess the effects of both abandonment and its proximity to managed fields. Ants were significantly more abundant in managed fields next to abandoned ones, though there were no differences between managed and abandoned fields. Spider abundance did not respond to abandonment nor proximity. Myriapods were more abundant in abandoned fields during the first sampling period, but the proximity of an abandoned field had no effect. Carabids were more abundant in managed fields, especially those adjacent to other managed fields. These results indicate that arthropod responses to abandonment are taxon-specific, highlighting that a mosaic of managed and abandoned fields can both enhance and reduce olive fruit fly predator abundance. Conservation strategies should integrate varying management intensities to optimize biodiversity in Mediterranean agroecosystems. Future research should investigate long-term effects and specific predator responses to abandonment.

Foreign Body Immune Response to Zwitterionic and Hyaluronic Acid Granular Hydrogels Made with Mechanical Fragmentation.

Granular hydrogels have recently attracted the attention for diverse tissue engineering applications due to their versatility and modularity. Despite previous studies showing enhanced viability and metabolism of cells encapsulated in these hydrogels, the in vitro immune response and long-term fibrotic response of these scaffolds have not been well characterized. Here, bulk and granular hydrogels are studied based on synthetic zwitterionic (ZI) and natural polysaccharide hyaluronic acid (HA) made with mechanical fragmentation. In vitro, immunomodulatory studies show an increased stimulatory effect of HA granular hydrogels compared to bulk, while both bulk and granular ZI hydrogels do not induce an inflammatory response. Subcutaneous implantation in mice shows that both ZI and HA granular hydrogels resulted in less collagen capsule deposition around implants compared to bulk HA hydrogels 10 weeks after implantation. Moreover, the HA granular hydrogels are infiltrated by host cells, including macrophages and mature blood vessels, in a porosity-dependent manner. However, a large number of cells, including multinucleated giant cells as well as blood vessels, surround bulk and granular ZI hydrogels and are not able to infiltrate. Overall, this study provides new insights on the long-term stability and fibrotic response of granular hydrogels, paving the way for future studies and applications.

Effectiveness of long-term bimekizumab treatment and predictive factors for responders in moderate-to-severe psoriasis: A 52-week real-world study.

Psoriasis is a chronic, inflammatory skin disease in which the interleukin (IL)-23/IL-17 axis plays a central role. Bimekizumab is a novel antibody that targets both IL-17A and IL-17F. This retrospective study aimed to assess the long-term effectiveness and safety of 52-week treatment with bimekizumab, and to identify predictive factors for short- (16 weeks) and long-term (52 weeks) responders (i.e., achievers of a Psoriasis Area and Severity Index (PASI) score of 100) to bimekizumab in Japanese patients with psoriasis. The study was conducted on 56 Japanese patients (aged ≥ 15 years) with moderate-to-severe psoriasis treated with bimekizumab from May 2022 to March 2024. The therapeutic effectiveness was evaluated by the transition of PASI scores during treatment. Baseline characteristics and clinical and laboratory indexes were compared between responders and poor responders. Treatment-emergent adverse events (TEAEs) were recorded to assess the safety of the treatment. At week 52, the achievement of PASI 100, static Physician's Global Assessment 0/1, and the Dermatology Life Quality Index 0/1 were 72.4%, 94.7%, and 93.3%, respectively. Short-term responders showed lower baseline values of neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio (MLR), and systemic inflammatory response index compared to poor responders. Long-term responders showed younger age and lower MLR compared to poor responders. TEAEs were mild or moderate, without serious adverse events. Long-term treatment with bimekizumab is effective and safe for psoriasis patients. Lower MLR and younger age might predict long-term response to treatment with bimekizumab, aiding in personalized treatment strategies.

Long-term Responders to Nanoparticle Albumin-bound Paclitaxel Following Immune Checkpoint Inhibitor in Non-small Cell Lung Cancer.

The efficacy of cytotoxic chemo-therapy has been reported to improve after immune checkpoint inhibitor (ICI) administration. We previously conducted a multicenter prospective clinical study to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-PTX) after ICI treatment. In that study, some patients showed a long-term response to nab-PTX, which is not usually observed with single-agent chemotherapy. The present study aimed to evaluate the clinical characteristics of these patients. We retrospectively analyzed updated data from 29 patients enrolled in our clinical study who received nab-PTX monotherapy after ICI treatment. We defined a "long-term responder" as a patient who achieved a 1-year progression-free survival (PFS). Among the 29 patients, 10 (34.5%) were long-term responders, two of whom achieved a 5-year PFS. A key difference between long-term and non-long-term responders was that the long-term responders had a significantly higher number of patients with Eastern Cooperative Oncology Group-performance status of 0 (70.0% versus 10.5%; p=0.002). Furthermore, median cycles of previous ICIs and median treatment cycles were significantly higher in long-term responders than in non-long-term responders (8 cycles versus 3 cycles; p=0.03) (5.9 months versus 2.0 months; p=0.02). In the 10 long-term responders, six patients required at least a one-stage dose reduction owing to adverse events, and four patients required a two-stage dose reduction. Nab-PTX administration after ICI treatment may elicit a long-term response. A long-term response can be achieved even with a dose reduction due to adverse events.

Updated Survival Follow-Up for Phase Ib Trial of the Histone Deacetylase Inhibitor Abexinostat With Pazopanib in Patients With Solid Tumor Malignancies.

Histone deacetylase (HDAC) inhibition downregulates hypoxia-inducible factor-1α and modulates multiple metabolomic pathways relevant in cancer. Here we report a potential novel biomarker to predict exceptional responders (>3 years) in patients receiving HDAC and vascular endothelial growth factor (VEGF) inhibition. Patients with solid tumor malignancies were enrolled in this phase Ib trial of abexinostat (4/7 ×21 days) and pazopanib (28/28 days), with a dose expansion in renal cell carcinoma (RCC). Plasma was analyzed for metabolomics and peripheral blood mononuclear cells (PBMCs) for VEGF and HDAC2 expression levels. Fifty-one patients were enrolled: n = 36 patients in dose escalation and n = 15 in dose expansion. After the initial report in 2017, six patients had remained on study: four with RCC and one each with medullary thyroid and thymic neuroendocrine carcinoma. One patient with RCC remains on treatment for >11 years after progression on five systemic therapies. Overall, the median duration of therapy measured 5.6 (1-133) months. The median duration of therapy in exceptional responders measured 44.1 (39.8-133+) months. The median overall survival in patients with high PBMC HDAC2 expression versus low HDAC2 was 32.3 versus 9.2 months (P = .004) for all patients and 43.3 versus 25.1 months for patients with RCC (P = .09). Exceptional responders had lower kynurenine levels both pre- and post-treatment (P = .002, P < .001, respectively). HDAC2 and kynurenine expression levels were inversely correlated (P = .02). Abexinostat added to pazopanib shows extended tolerability and long-term responses and survival. PBMC HDAC2 levels, the abexinostat target, are relevant predictors of response. In addition, metabolomic assessment points to kynurenine as a predictor for exceptional response to combined VEGF plus HDAC inhibition.

Magnitude of antigen-specific T-cell immunity the month after completing vaccination series predicts the development of long-term persistence of antitumor immune response

BackgroundFor best efficacy, vaccines must provide long-lasting immunity. To measure longevity, memory from B and T cells are surrogate endpoints for vaccine efficacy. When antibodies are insufficient for protection, the...

Bank-firm common ownership, green credit and enterprise green technology innovation: Evidence from Chinese credit markets

Bank-firm common ownership can tackle the innovation dilemma of bank loans on firms' green development. This paper constructs indicators of common ownership and green technological innovation and then investigates the impact of bank-firm common ownership on corporates' green technological innovation using Chinese A-share listed enterprises samples from 2004 to 2021. Our conducted experiments reveal that bank-firm common ownership shareholders not only make banks and lending firms have the same goal, promote the total level, quantity, and quality of technological innovation for the green development of lending firms, and profit from the firms' short- and long-term market responses. Our findings are prominent in private enterprises, small-capitalization enterprises, and bull market cycles. In addition, we discover that shareholder reduction restrictions and policies restricting corporate shareholding in financial institutions enhance bank-firm common ownership shareholders on corporate green technological innovation development. Common ownership shareholders reduce information asymmetry between banks and lending enterprises and provide green loans to support enterprise green technology innovations. Furthermore, alleviating financing constraints and strengthening the supervisory role are important influence mechanisms. In this regard, carried PSE analysis indicates the direct effect of bank-firm common ownership shareholders to promote enterprise green development of technological innovation accounts for about 14 % of the total effect, the intermediary effect of “financing mechanism” and “supervision mechanism” account for about 82 % and 4 %, and the “financing mechanism” is more important than the “supervision mechanism.” The findings of this paper can optimize the credit market to serve the green and high-quality development of Chinese enterprises better.

Association of testosterone replacement therapy with atrial fibrillation and acute kidney injury.

Secondary analyses of the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial revealed significantly higher rates of new-onset atrial fibrillation (AF) and acute kidney injury (AKI) in the testosterone replacement therapy (TRT) cohort. To validate the secondary findings of the TRAVERSE trial. We utilized the TriNetX Research Network to identify a cohort of men ages 45-80years old who met similar inclusion criteria to the TRAVERSE trial. We compared hypogonadal men (testosterone 100-300ng/dL) who had a prescription for topical testosterone therapy and men who did not. Propensity score matching was used to match patient populations. Kaplan Meier survival analysis was used to determine the relative risk of new-onset AF and AKI within 3years. New-onset AF and AKI within 3years. There were 2134 men included in each cohort after propensity score matching. Men on TRT had significantly lower testosterone (T) at the time of diagnosis compared to men not prescribed TRT (207 ± 66ng/dL vs 246 ± 140ng/dL, P< 0.001). Kaplan-Meier survival analysis showed a significantly increased risk of AKI among men on TRT (RR 1.53, 95% CI 1.07-2.18). However, TRT was not associated with a significantly increased risk of new-onset AF (RR 1.48, 95% CI 0.93-2.37). Hypogonadal men with underlying cardiovascular risk factors or pre-existing cardiovascular disease who receive TRT may be at increased risk of AKI after starting therapy. We evaluated a large global research database and utilized similar inclusion and exclusion to the TRAVERSE trial. However, our results are limited by the retrospective study design and reliance on documented claims data. Similar to the TRAVERSE trial, our study demonstrated an increased risk of AKI among men on TRT, but did not find increased risk of AF. However, further studies are required to validate these results.