Conditional deletion of Zeb1 in Csf1r+ cells reduces inflammatory response of the cornea to alkali burn.

ZEB1 is an essential factor in embryonic development. In adults, it is often highly expressed in malignant tumors with low expression in normal tissues. The major biological function of ZEB1 in developing embryos and progressing cancers is to transdifferentiate cells from an epithelial to mesenchymal phenotype; but what roles ZEB1 plays in normal adult tissues are largely unknown. We previously reported that the reduction of Zeb1 in monoallelic global knockout (Zeb1+/-) mice reduced corneal inflammation-associated neovascularization following alkali burn. To uncover the cellular mechanism underlying the Zeb1 regulation of corneal inflammation, we functionally deleted Zeb1 alleles in Csf1r+ myeloid cells using a conditional knockout (cKO) strategy and found that Zeb1 cKO reduced leukocytes in the cornea after alkali burn. The reduction of immune cells was due to their increased apoptotic rate and linked to a Zeb1-downregulated apoptotic pathway. We conclude that Zeb1 facilitates corneal inflammatory response by maintaining Csf1r+ cell viability.

Immunotherapy of targeting MDSCs in tumor microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells which are abnormally accumulated during the differentiation of myeloid cells. Immunosuppression is the main functional feature of MDSCs, which inhibit T cell activity in the tumor microenvironment (TME) and promote tumoral immune escape. The main principle for immunotherapy is to modulate, restore, and remodel the plasticity and potential of immune system to have an effective anti-tumor response. In the TME, MDSCs are major obstacles to cancer immunotherapy through reducing the anti-tumor efficacy and making tumor cells more resistant to immunotherapy. Therefore, targeting MDSCs treatment becomes the priority of relevant studies and provides new immunotherapeutic strategy for cancer treatment. In this review, we mainly discuss the functions and mechanisms of MDSCs as well as their functional changes in the TME. Further, we review therapeutic effects of immunotherapy against MDSCs and potential breakthroughs regarding immunotherapy targeting MDSCs and immune checkpoint blockade (ICB) immunotherapy.

Predictors of need for catheterisation and urinary retention after radical cystectomy and orthotopic neobladder in male patients.

OBJECTIVES: To investigate the prevalence of catheterisation and urinary retention in male patients with bladder cancer after radical cystectomy (RC) and orthotopic neobladder (ONB) and to identify potential predictors. PATIENTS AND METHODS: Using an Institutional Review Board approved, prospectively maintained bladder cancer database, we collected information using a diversion-related questionnaire from 299 consecutive male patients with bladder cancer upon postoperative clinic visit. Urinary retention was defined as ≥3 catheterisations/day or a self-reported inability to void without a catheter. Uni- and multivariable Cox regression analysis was performed to identify predictors of catheterisation and urinary retention. RESULTS: Self-catheterisation was reported in 51 patients (17%), of whom, 22 (7.4% of the total patients) were in retention. Freedom from any catheterisation at 3, 5, and 10 years after RC was 85%, 77%, and 62%, respectively. Freedom from retention at 3, 5, and 10 years after RC was 93%, 88%, and 79%, respectively. Multivariable Cox regression showed that higher body mass index (BMI; ≥27 kg/m2 ) significantly increased the need for catheterisation (hazard ratio [HR] 2.34, 95% confidence interval [CI] 1.26-4.32) as well as retention (HR 5.20, 95% CI 1.74-15.51). Greater medical comorbidity (Charlson Comorbidity Index score ≥2) correlated with the need for any catheterisation (HR 1.84, 95% CI 1.02-3.3), but not retention. Pathological stage and type of diversion were not significant predictors of the need to catheterise or urinary retention. CONCLUSION: In males undergoing RC with ONB, retention requiring catheterisation to void is uncommon. Patients with a BMI of ≥27 kg/m2 are at significantly increased risk of retention and need for self-catheterisation.

Restoring Condylar Width: Radiographic Relationship Between the Lateral Tibial Plateau and Lateral Femoral Condyle in Normal Adult Knees.

OBJECTIVES: We hypothesized that a constant radiographic relationship exists between the lateral tibial and femoral condyles and that no side-to-side variation exists. METHODS: We reviewed anteroposterior x-rays of 217 uninjured adults ages 18-65, Included 109 unilateral and 108 bilateral radiographs with no or minimal osteoarthrosis (Kellgren-Lawrence grades 0-1). The perpendicular distance between the lateral-most margins of the tibial plateau articular surface (A) and the lateral femoral epicondyle (B) and the lateral femoral condyle articular surface (C) was measured in millimeters (mm). Medial and lateral measurements to point (A) were recorded as (-) and (+), respectively. First, the average of measured distances in all unilateral knees and randomly selected either right or left knees from the bilateral group (n = 217) was calculated. Comparison was made between both sexes. Next, A-B and A-C distances were compared between right and left knees in the bilateral group (n = 108) to find any significant difference (2-tailed t test, alpha = 0.05). RESULTS: The average A-B distance was 0.60 ± 2.40 mm (-4.82 to +6.49 mm). The mean A-C distance was -3.96 ± 2.07 mm (-8.51 to +3.98 mm). No significant difference was found between A-B and A-C distances between males (0.40 ± 2.62 mm and -3.91 ± 2.05 mm) and females (0.70 ± 2.28 mm and -3.99 ± 2.09 mm). Similarly, no significant difference was found between A-B and A-C distances between right (1.08 ± 2.31 mm and -3.90 ± 1.73 mm) and left knees (0.90 ± 2.38 mm and -4.31 ± 1.7 mm). Concordance coefficient for interobserver and intraobserver reliability showed substantial agreement. CONCLUSION: In conclusion, this study provided a "normal" range for the relationship of the proximal lateral tibial plateau relative to the lateral femoral condyle. The lateral femoral epicondyle is generally aligned with the lateral tibial articular margin. The relationship between the lateral tibial plateau, lateral femoral epicondylar surface, and lateral femoral articular surface is constant from side to side. This technique is reproducible in the setting of fracture, and templating off of the contralateral uninjured knee may be beneficial in tibial plateau fracture surgery.

A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation-contraction coupling in the mouse heart.

Evidence supports the expression of brain-type sodium channels in the heart. Their functional role, however, remains controversial. We used global Na(V)1.6-null mice to test the hypothesis that Na(V)1.6 contributes to the maintenance of propagation in the myocardium and to excitation-contraction (EC) coupling. We demonstrated expression of transcripts encoding full-length Na(V)1.6 in isolated ventricular myocytes and confirmed the striated pattern of Na(V)1.6 fluorescence in myocytes. On the ECG, the PR and QRS intervals were prolonged in the null mice, and the Ca(2+) transients were longer in the null cells. Under patch clamping, at holding potential (HP) = -120 mV, the peak I(Na) was similar in both phenotypes. However, at HP = -70 mV, the peak I(Na) was smaller in the nulls. In optical mapping, at 4 mM [K(+)](o), 17 null hearts showed slight (7%) reduction of ventricular conduction velocity (CV) compared to 16 wild-type hearts. At 12 mM [K(+)](o), CV was 25% slower in a subset of 9 null vs. 9 wild-type hearts. These results highlight the importance of neuronal sodium channels in the heart, whereby Na(V)1.6 participates in EC coupling, and represents an intrinsic depolarizing reserve that contributes to excitation.

Synthetic triterpenoid CDDO prevents the progression and metastasis of prostate cancer in TRAMP mice by inhibiting survival signaling.

In an extension of our previous studies showing potent antitumorigenic activity of synthetic triterpenoids of oleanolic acid against prostate cancer cell lines, we examined the efficacy of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) in preventing the development and/or progression of prostate cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Data show that oral gavage with CDDO (10 µmol/kg) for 20 weeks resulted in inhibition of the progression of preneoplastic lesions in the dorsolateral prostate and ventral prostate to adenocarcinoma without toxicity. CDDO also inhibited metastasis of tumor to the distant organs. Treatment with CDDO significantly inhibited cell proliferation, reduced the density of blood vessels and promoted apoptosis in the prostatic tissue. Further, Akt, NF-κB and NF-κB regulated Bcl-2, Bcl-xL, survivin and cIAP1 appear to be the molecular targets of CDDO for inhibiting the progression of prostate cancer in TRAMP mice. Thus, these studies show for the first time the potential of CDDO for chemoprevention of human prostate cancer.