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Immune checkpoint blockade (ICB) of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint pathway has led to unprecedented advances in cancer therapy. However, the overall response rate of anti-PD-1/PD-L1 monotherapy is still unpromising, underscoring the need for predictive biomarkers. In this retrospective study, we collected pretreatment plasma samples from two independent cohorts of patients receiving ICB. To determine whether a signature of plasma cytokines could be associated with therapeutic efficacy, we systemically profiled cytokine clusters and functional groups in the discovery and validation datasets by using 59 multiplexed bead immunoassays and bioinformatics analysis. We first attempted to functionally classify the 59 immunological factors according to their biological classification or functional roles in the cancer-immunity cycle. Surprisingly, we observed that two signatures, the "checkpoint signature" and "trafficking of T-cell signature", were higher in the response subgroup than in the nonresponse subgroup in both the discovery and validation cohorts. Moreover, enrichment of the "checkpoint signature" was correlated with improved overall survival and progression-free survival in both datasets. In addition, we demonstrated that increased baseline levels of three checkpoint molecules (PD-L1, T-cell immunoglobulin mucin receptor 3 and T-cell-specific surface glycoprotein CD28) were common peripheral responsive correlates in both cohorts, thus rendering this "refined checkpoint signature" an ideal candidate for future verification. In the peripheral blood system, the "refined checkpoint signature" may function as a potential biomarker for anti-PD-1/PD-L1 monotherapy in gastrointestinal (GI) cancers. [ABSTRACT FROM AUTHOR]

This study explores change of precipitation and temperature using the Mann-Kendall test and the spatiotemporal variation of dryness/wetness using the standardized precipitation evapotranspiration index and empirical orthogonal function (EOF) analysis on 1-month time scales in Zhejiang Province, China, over 1971-2015. The results show that monthly precipitation had significant decreasing trends during April, May, September, and October, and significant increasing trends during November and December. Monthly temperatures had significant increasing trends in each month. Increasing temperature significantly increased drought events and intensity. There were consistent spatial patterns of dryness/wetness in Zhejiang. There were dryness trends in April, May, and September, a wetness trend in August, and no dryness/wetness pattern change in other months. The second EOF modes showed that dryness/wetness patterns were anti-phase between northern and southern Zhejiang during April-October. The third EOF modes showed that patterns were anti-phase between eastern and western Zhejiang in August and September. [ABSTRACT FROM AUTHOR]

Based on phenological and economic output models established and meteorological data from 1972 to 2013, changes in the phenology, frost risk, and economic output of the Longjing-43 tea tree in the Yuezhou Longjing tea production area of China were evaluated. As the local climate has changed, the beginning dates of tea bud and leaf plucking of this cultivar in all five counties studied has advanced significantly by −1.28 to −0.88 days/decade, with no significant change in the risk of frost. The main tea-producing stages in the tea production cycle include the plucking periods for superfine, grade 1, and grade 2 buds and leaves. Among the five bud and leaf grades, the economic output of the plucking periods for superfine and grade 1 decreased significantly, that for grade 2 showed no significant change, and those for grades 3 and 4 increased significantly. The economic output of large-area tea plantations employing an average of 45 workers per hectare and producing superfine to grade 2 buds and leaves were significantly reduced by 6,745-8,829 yuan/decade/ha, depending on the county. Those tea farmers who planted tea trees on their own small land holdings and produced superfine to grade 4 tea buds and leaves themselves experienced no significant decline in economic output. [ABSTRACT FROM AUTHOR]

Immunotherapy has emerged as an effective therapeutic strategy for various cancers, including colorectal cancer (CRC), but only a subset of MSI-H patients can benefit from such therapy. Patched1 (PTCH1) is a frequently altered gene in CRCs and its mutations contribute to unregulated Hedgehog (Hh) signaling. In the study, we evaluated the association of PTCH1 mutations with CRC immunity based on our single-center cohort and multiple cancer genomic datasets. Among 21 enrolled patients, six (28.6%) harbored a PTCH1 mutation based on WES analyses. In CRC patients, the PTCH1 mutation subgroup experienced a higher durable clinical benefit rate than the PTCH1 wild-type subgroup (100% vs. 40%, P = 0.017). In addition, patients with the PTCH1 mutation experienced greater progression-free survival (PFS, P = 0.037; HR, 0.208) and overall survival (OS, P = 0.045; HR, 0.185). A validation cohort from the MSKCC also confirmed the correlation between PTCH1 mutation and better prognosis (P = 0.022; HR, 0.290). Mechanically, diverse antitumor immune signatures were more highly enriched in PTCH1-mutated tumors than in PTCH1 wild-type tumors. Furthermore, PTCH1-mutated tumors had higher proportions of CD8 + T cells, activated NK cells, and M1 type macrophage infiltration, as well as elevated gene signatures of several steps in the cancer-immunity cycle. Notably, the PTCH1 mutation was correlated with tumor mutational burden (TMB), loss of heterozygosity score, and copy number variation burden. Our results show that the mutation of PTCH1 is a potential biomarker for predicting the response of CRC patients to immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze the impact of different biopsy protocols on the rate of mosaic blastocysts. Methods: This is a retrospective cohort study which included 115 cycles with pre-implantation genetic testing for aneuploidy (PGT-A). Two groups were allocated based on the biopsy protocols: method 1 group, the zona pellucida (ZP) was drilled on day 3 embryos followed by trophectoderm (TE) biopsy; and method 2 group, the ZP was opened on day 5 or 6 blastocysts followed by TE biopsy. All biopsy samples were assessed using next-generation sequencing (NGS) at a single reference laboratory. The euploid, aneuploid, and mosaic blastocyst rates and clinical outcomes were compared. Results: The mosaicism rate in the method 1 group was 19.58%, significantly higher than the method 2 group (8.12%; P < 0.05). No statistically significant difference was observed in euploid, aneuploid blastocyst rates, and clinical pregnancy rates between the two groups. Logistic regression analysis indicated that the biopsy protocols were independently associated with the mosaicism rates among all the variables. Conclusions: The present study showed that different biopsy protocols may have an impact on the mosaic blastocyst rate. ZP opening on day 3 combined with TE biopsy might increase the incidence of mosaic blastocysts. [ABSTRACT FROM AUTHOR]