The receptor programmed death 1 (PD-1) inhibits T cell proliferation and plays a critical role in suppressing self-reactive T cells, and it also compromises antiviral and antitumor responses. To determine how PD-1 signaling inhibits T cell proliferation, we used human CD4+ T cells to examine the effects of PD-1 signaling on the molecular control of the cell cycle. The ubiquitin ligase SCFSkp2 degrades p27kip1, an inhibitor of cyclin-dependent kinases (Cdks), and PD-1 blocked cell cycle progression through the G1 phase by suppressing transcription of SKP2, which encodes a component of this ubiquitin ligase. Thus, in T cells stimulated through PD-1, Cdks were not activated, and two critical Cdk substrates were not phosphorylated. Activation of PD-1 inhibited phosphorylation of the retinoblastoma gene product, which suppressed expression of E2F target genes. PD-1 also inhibited phosphorylation of the transcription factor Smad3, which increased its activity. These events induced additional inhibitory checkpoints in the cell cycle by increasing the abundance of the G1 phase inhibitor p15INK4 and repressing the Cdk-activating phosphatase Cdc25A. PD-1 suppressed SKP2 transcription by inhibiting phosphoinositide 3-kinase–Akt and Ras–mitogen-activated and extracellular signal–regulated kinase kinase (MEK)–extracellular signal–regulated kinase (ERK) signaling. Exposure of cells to the proliferation-promoting cytokine interleukin-2 restored activation of MEK-ERK signaling, but not Akt signaling, and only partially restored SKP2 expression. Thus, PD-1 blocks cell cycle progression and proliferation of T lymphocytes by affecting multiple regulators of the cell cycle.

ObjectiveFibroblast activation protein (FAP) plays a vital role in tumor invasion and metastasis. Previous studies have reported its prognostic value in different tumors. However, the results of these reports remain controversial. In this study, a meta-analysis was performed to clarify this issue.MethodsA search of the PubMed, Embase and CNKI databases was conducted to analyze relevant articles. The outcomes included the relations between FAP expression and histological differentiation, tumor invasion, lymph node metastasis, distant metastasis and overall survival (OS). Sensitivity analysis by FAP expression in different cells and tumor types were further subjected to sensitivity analyses as subgroups. Pooled odds ratios (ORs) and hazard ratios (HRs) were evaluated using the random-effects model.ResultsThe global analysis included 15 studies concerning various solid tumors. For global analysis, FAP overexpression in tumor tissue displayed significant associations with poor OS and tumor progression (OS: HR = 2.18, P = 0.004; tumor invasion: OR = 4.48, P = 0.007; and lymph node metastasis: OR = 3.80, P = 0.004). The subgroup analyses yielded two notable results. First, the relation between FAP overexpression and poor OS and tumor lymph node metastasis was closer in the patients with FAP expression in tumor cells. Second, the pooled analyses of colorectal cancers or pancreatic cancers all indicated that FAP overexpression was associated with a detrimental OS (HR: 1.72, P = 0.009; HR: 3.18, P = 0.005, respectively). The magnitude of this effect was not statistically significant compared with that in patients with non-colorectal cancers or non-pancreatic cancers. These analyses did not display a statistically significant correlation between FAP expression and histological differentiation and distant metastasis in all of the groups.ConclusionsFAP expression is associated with worse prognosis in solid tumors, and this association is particularly pronounced if FAP overexpression is found in the tumor cells rather than the stroma.

AIM:To investigate the expression of annexin I in pancreatic cancer and its relationship with the clinicopathologic factors, and to evaluate its potential clinical significance.

To determine incidence and clinically relevant risk factors for diabetic amputation in a large cohort study of diabetic foot ulceration patients in China, we investigated a total of 669 diabetic foot ulceration patients, who were assessed at baseline for demographic information, medical and social history, peripheral neuropathy screening, periphery artery disease screening, assessment of nutritional status and diabetic control, physical examination including foot deformity in 15 Grade III-A hospitals. Of the 669 patients, 435 were male and 201 were female, with the mean age being 64.0 years. Of all patients, 110 had neuropathic ulcers, 122 had ischemic ulcers, 276 had neuroischemic ulcers, and 12 cases were unclassified. Wagner classification showed 61 cases were grade I, 216 cases grade II, 159 cases grade III, 137 cases grade IV, and 7 cases grade V. The overall amputation rate among diabetic foot patients was 19.03%, and major and minor amputation rates were 2.14% and 16.88%, respectively. By univariate analysis, statistically significant differences were found in smoking, rest pain, ulcer history, revascularization history, amputation history, gangrene, infection, Wagner grades, duration of diabetes, and postprandial blood glucose, aldehyde, total protein, globulin, albumin, white blood cell (WBC), hemoglobin, HbA1c, ulcer property, body mass index, as well as creatinine. Binary logistic regression model showed that increased WBC (odds ratio 1.25) and ulcer history (odds ratio 6.8) were associated with increased risks from diabetic foot ulcer to major amputation; increased duration of diabetes (odds ratio 1.004), WBC (odds ratio 1.102), infection (odds ratio 2.323), foot deformity (odds ratio 1.973), revascularization history (odds ratio 2.662), and decreased postprandial blood sugar (odds ratio 0.94) were associated with increased risks from diabetic foot ulcer to minor amputation. It is of great importance to give better management to diabetic patients at early stages. Following a diagnosis of DFU more intensive surveillance and aggressive care may improve outcome.

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