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BACKGROUND: Accumulating evidence shows that the increase in blood viscosity (BV) is an independent risk factor for atherosclerosis and its related diseases, but as far as we know, there are few studies on the relationship between blood viscosity and carotid plaque severity. Therefore, we aimed to investigate the relationship between blood viscosity and the presence of carotid plaques, and further explore its relationship with the severity of carotid plaques. METHODS: We retrospectively analyzed the data of consecutive subjects in the physical examination center of the Affiliated Hospital of Ningbo University Medical College from January 2022 to May 2022. The parameters of blood viscosity include the whole blood viscosity (WBV) at high, middle, and low shear rate, plasma viscosity (PV), hematocrit (HCT), rigidity “k”, rigidity index (RI), aggregation index (AI) and electrophoresis rate (ER), and standardized BV calculated by Quemada’s equation were included in the study. Carotid plaque score (CPS) was used to measure the severity of carotid artery disease, and participants were divided into mild, moderate, and severe groups according to the quartile of the score. Independent samples t-test and one-way ANOVA were used to compare normally distributed continuous variables between two or more independent groups, respectively. Binary logistic regression was used to evaluate the risk factors of carotid plaque. RESULTS: 314 men were enrolled in the study, of which 165 participants were diagnosed with Carotid artery plaque (CAP) (66.9%). Compared with the CAP- group, the WBV and PV of the CAP+group decreased, but the difference only existed in the PV (p = 0.001). However, standardized BV values (HCT set at 0.45) were higher in the CAP+group than in the CAP- group (3.8643±0.35431vs 3.9542±0.64871, p = 0.188). Regarding the rigidity and aggregation of RBC, the parameters including rigidity “k”, RI, AI and ER increased in the CAP+group compared with the CAP- group. The difference was statistically significant in k and ER (p = 0.04, p = 0.009). To assess the severity of carotid plaque, we divided the participants into mild, moderate, and severe groups by using the tertile of CPS value. The mild group was defined as CPS≤0.5 (n = 108), the moderate group as 0.5 1.7 (n = 101). It was found that WBV and PV decreased with the increase of plaque severity, but the difference among the three groups was significant in PV (F = 8.073, p

Supplementary figures 1-10. Figure S1. IL-2c increases conventional CD4 T cell in ascites three weeks after final IL-2c, but does not affect ascites Treg and effector T cell numbers at one week after final IL-2c administration. Figure S2. IL-2c treatment increases CD8+ central and effector memory T cells in the ascites, and central memory T cells in TDLN. Fig S3. Additional Treg phenotype in ascites and TDLN after IL-2c treatment. Fig S4. IL-2c directly inhibits Treg suppression specifically in the tumor microenvironment. Fig S5. IL-2 signaling is not impaired in TDLN after IL-2c treatment. Figure S6. Specific Treg depletion is highly effective against ID8agg. Figure S7. αCD25 attenuates IL-2c-induced tumor rejection and T cell function in ID8agg OC. Figure S8. IL-2c promotes intratumoral T cell infiltration. Figure S9. IL-2c reduces intratumoral Treg activation and functional molecules in B16 melanoma. Figure S10. IL-2c increases TIGIT+LAG-3+PD-1+ CD8+ T cells in B16 tumors.

An enantioselective synthesis of tiagabine has been achieved utilizing an asymmetric hydrogen atom transfer protocol to construct its essential chiral tertiary carbon center. A cyclization reaction via double N-substitution is tactically orchestrated as the other key step to install the crucial alkaloid ring. Compared with the previous synthetic strategy, which used commercially available nicotinate as the starting material to ensure a short synthetic route, this strategy uses a readily modifiable and accessible alkyl-substituted acrylate as the starting material and thus provides a scenario for the facile synthesis of analogues and derivatives of tiagabine for further biological research.

Asymmetric hydrogen atom transfer (HAT) represents arguably one of the most straightforward access to the significant chiral tertiary carbon centers, however, remains a long-standing challenge. Herein, the first example of catalytic coordination-induced asymmetric HAT reaction has been developed relying on a sequential (salen)Ti

The IL2 receptor (IL2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Treg) and antitumor T cells. Here we used IL2Rβ-selective IL2/anti-IL2 complexes (IL2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer model. Despite strong tumor rejection, IL2c unexpectedly lowered the tumor microenvironmental CD8+/Treg ratio. IL2c reduced tumor microenvironmental Treg suppression and induced a fragile Treg phenotype, helping explain improved efficacy despite numerically increased Tregs without affecting Treg in draining lymph nodes. IL2c also reduced Treg-mediated, high-affinity IL2R signaling needed for optimal Treg functions, a likely mechanism for reduced Treg suppression. Effector T-cell IL2R signaling was simultaneously improved, suggesting that IL2c inhibits Treg functions without hindering effector T cells, a limitation of most Treg depletion agents. Anti-PD-L1 antibody did not treat ID8agg, but adding IL2c generated complete tumor regressions and protective immune memory not achieved by either monotherapy. Similar anti-PD-L1 augmentation of IL2c and degradation of Treg functions were seen in subcutaneous B16 melanoma. Thus, IL2c is a multifunctional immunotherapy agent that stimulates immunity, reduces immunosuppression in a site-specific manner, and combines with other immunotherapies to treat distinct tumors in distinct anatomic compartments. Significance: These findings present CD122-targeted IL2 complexes as an advancement in cancer immunotherapy, as they reduce Treg immunosuppression, improve anticancer immunity, and boost PD-L1 immune checkpoint blockade efficacy in distinct tumors and anatomic locations.

The objective of this study is to explore the prognostic factors of double primary cancer patients with lung cancer as the first primary cancer (FPC). The Surveillance, Epidemiology, and End Results (SEER) database is a database established by the National Institutes of Research for cancer registration purposes, which collects relatively complete demographic characteristics and clinical data for assessing the epidemiological characteristics of cancer worldwide. Clinical data on patients with a clear histopathological diagnosis of double primary with lung cancer as the FPC were identified and collected from the SEER database from 2010 to 2015. Survival curves were plotted by Kaplan-Meier survival analysis. Independent prognostic factors of patients were analyzed by COX proportional risk model. Clinical data were collected from a total of 9306 patients, including 6516 patients in the modeling group and 2790 patients in the validation group. When we retrieved that the FPC was lung cancer, we found that the most common site of the second primary cancer was located in the respiratory system (54.0%). In addition, the most common site of first primary lung cancer in patients with double primary cancer was the right upper lobe (33.3%). A total of 14 independent prognostic factors were included, and the constructed survival nomogram had high accuracy and clinical applicability. The nomogram established in this study can help to raise awareness of clinical workers and the importance of such diseases, and guide the treatment and follow-up strategies.

The IL-2 receptor (IL-2R) is an attractive target for cancer immunotherapy as it controls both immune-suppressive regulatory T cells (Tregs) and anti-tumor T cells. We tested depleting Tregs as immunotherapy using anti-CD25 (high-affinity IL-2R subunit) antibodies (αCD25) in ID8agg mouse ovarian cancer (OC). αCD25 reduced ascites and Treg numbers but failed to reduce tumor burden, possibly because it depleted newly activated anti-tumor T cells in tumor-draining lymph nodes. Thus, αCD25 could be novel malignant ascites palliation, but has limited stand-alone efficacy. We then tested IL-2/anti-IL-2 complexes (IL-2c) that selectively stimulate medium-affinity (CD122/CD132) IL-2R thought to expand anti-tumor T cells preferentially, but with little Treg effects. In contrast to several single agents we tested that failed to treat ID8agg (e.g., αCD25, αPD-L1, IL-2 fusion toxin denileukin diftitox), IL-2c alone durably reduced ID8agg tumor burden despite lowering the tumor microenvironmental CD8+/Treg ratio. Thus, we hypothesized that IL-2c improved CD8+ function, reduced Treg function, or both. IL-2c increased polyfunctional IFN-γ+TNF-α+ anti-tumor T cells as expected, an effect that persists weeks after drug clearance. IL-2c also increased anti-tumor T cell CD25 expression that increased IL-2 sensitivity and STAT5 phosphorylation, a likely mechanism for increased polyfunctionality. Unexpectedly, IL-2c reduced the Treg functional mediators CD25, TIGIT and granzyme B, and reduced Treg suppressive function. Thus, favorable Treg modifications are a novel IL-2c mechanism of action. Adding αCD25 to IL-2c to deplete Tregs further unexpectedly worsened IL-2c efficacy in ID8agg and reduced effector memory T cells and polyfunctional T cells in the tumor microenvironment, suggesting a previously unappreciated role for CD25 in IL-2c therapy. Similar data were seen in B16 melanoma, suggesting αCD25 reduction of IL-2c efficacy is not tumor or compartment-specific (ID8agg is peritoneal and B16 is subcutaneous). αPD-L1, an ineffective monotherapy in ID8agg, combined with IL-2c to promote complete responses, suggesting potential for potent, novel combinatorial approaches. Our data suggest that antagonizing high affinity IL-2R (such as to deplete Tregs with αCD25) has limited cancer immunotherapy utility without more specific Treg targeting. In contrast, stimulating medium-affinity IL-2R with CD122-selective IL-2c has great translational promise by simultaneously improving beneficial anti-tumor T cells and reducing detrimental Treg function. Citation Format: Justin M. Drerup, Sri Lakshmi Pandeswara, Aijie Liu, Curtis A. Clark, Alvaro S. Padron, Wanjiao Chen, Vincent Hurez, Tyler J. Curiel. CD122-selective IL-2/anti-IL-2 complexes reduce regulatory T cell function and promote CD8+ T cell polyfunctionality for durable ovarian cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1608. doi:10.1158/1538-7445.AM2017-1608

We tested microencapsulated rapamycin (eRapa, ~2.2 mg/kg rapamycin/mouse/day) in carcinogen (azoxymethane, AOM) + inflammatory agent (dextran sodium sulfate, DSS) colon cancer. WT BL6 mice fed eRapa before, and during AOM/DSS had significantly fewer colon tumors and tumor burden than control fed mice (empty microcapsules). eRapa prevented colon cancer in δ TCR KO mice lacking γδ T cells but not in IFN-γ KO mice. In carcinogen (DMBA) + inflammatory agent (TPA) skin cancer, IFN-γ and γδ T cells were both needed for eRapa cancer prevention, showing tumor-specific and common immune requirements for eRapa-mediated cancer prevention. In βδ TCR KO mice lacking all T cells, AOM/DSS induced no cancer or only few tumors, suggesting αβ T cells are required for colon neoplasia and cancer in the AOM/DSS model. Protection from acute colitis in this model usually predicts colon cancer protection. Strikingly, however, eRapa did not prevent acute clinical or histologic colitis induced by DSS, despite cancer protection, suggesting effects on chronic colitis, or induction of cancer-protective but not acute colitis-protective mechanisms. In acute colitis, eRapa significantly decreased spleen and colon weights and CD3+CD4+ T cells, and increased mesenteric lymph node γδ T cells (with decreased Vγ1.1+ and increased Vγ2+ subsets) consistent with altered inflammation and reduced CD4-CXCR3+ and CD4-α4β7 T cells (likely γδ T cells) consistent with altered trafficking but did not affect CCR9+ T cells. In chronic colitis, eRapa significantly increased γδ T cells (with no changes in Vγ1.1+ or Vγ2+ subsets) that could mediate cancer protection. These novel immune effects of rapamycin help define its cancer prevention mechanisms and define novel clinical uses.

We used a defined IL-2/αIL-2 complex that directs IL-2 to stimulate only intermediate-affinity IL-2 receptor (CD122/132) to promote tumor rejection and avoid regulatory T cell (Treg) expansion. However, it is unknown if IL-2/αIL-2 alters Treg function, as Tregs also express CD122/132. After challenge with ID8agg ovarian cancer (OC) cells, IL-2/αIL-2 greatly reduced tumor burden, and increased IFN-γ, TNF-α, CD44, and CD25 in CD4+ non-Tregs and CD8+ T cells, as expected. IL-2/αIL-2 was clinically effective, yet it lowered the ascites CD8+/FoxP3+ Treg ratio and increased per cell FoxP3 levels in Tregs, suggesting a change in Treg function. IL-2/αIL-2 decreased the ratio of CD62L+ central Tregs to CD44+ effector Tregs in ID8agg ascites, indicating modulation of Treg differentiation. Surprisingly, ascites Tregs produced IFN-γ, IL-2, and TNF-α in control-treated OC mice, which was abolished by IL-2/αIL-2, suggesting further alteration of Treg differentiation and function. CD25 (high-affinity IL-2 receptor subunit) expression on Tregs was reduced by IL-2/αIL-2, which could lower Treg IL-2 sequestration and increase IL-2 available to antitumor T cells. CD25 blockade with αCD25 during IL-2/αIL-2 treatment reduced clinical efficacy but greatly increased central memory (CM; CD62L+CD44+) CD8+ T cells in blood and mesenteric (tumor-draining) lymph nodes. Thus, reduction of tumor burden by IL-2/αIL-2 is associated with reprogramming of Treg differentiation and function in an OC model. CD25 blockade after IL-2/αIL-2 could improve response durability by boosting CM CD8+ formation. These data demonstrate novel effects of IL-2-modulating drugs on Tregs and CD8+ memory and will aid development of more effective anticancer immunotherapy.