Wet age-related macular degeneration(wARMD)emerges as a primary contributor to irreversible vision impairment in the aging demographic. In clinical practice, anti-vascular endothelial growth factor(VEGF)therapies exhibit pronounced success in managing wARMD. However, in the actual clinical application, there are significant individual differences in the prognosis of anti-VEGF drug therapy, and some patients show poor response to the treatment, which may be related to the morphological differences of retinal layers in macular area, genetics, systemic conditions and other factors. It will help develop a more rational and individualized treatment plan to judge the prognosis of patients according to their different clinical manifestations in advance, so as to reduce overtreatment and the risk of retinal damage. In recent years, most studies on treatment response mainly focus on fundus morphology, genetics and so on. In this study, the relevant factors affecting adverse response to wARMD were reviewed, aiming to provide with more accurate treatment and prognostic monitoring programs for clinicians.

BACKGROUND: Periodontitis is a severe chronic inflammatory disease, whose traditional systemic antimicrobial therapy faces great limitations. In-situ gels provide an effective solution as an emerging local drug delivery system. METHODS: In this study, the novel thermosensitive poloxamer/carbopol in-situ gels loaded with 20 lmol/L quercetin for the treatment of periodontitis were prepared by cold method. Thirteen batches of in-situ gels based on two independent factors (X1 : poloxamer 407 and X2 : carbopol 934P) were designed and optimized by the statistical method of central composite design (CCD). The transparency, pH, injectability, viscosity, gelation temperature, gelation time, elasticity modulus, degradation rate and in-vitro drug release studies of the batches were evaluated, and the percentage of drug release in the first hour, the time required for 90% drug release, gelation temperature, and gelation time were selected as dependent variables. RESULTS: These two independent factors significantly affected the four dependent variables (p < 0.05). The optimization result displayed that the optimized concentration of poloxamer 407 was 20.84% (w/v), and carbopol 934P was 0.5% (w/v). The optimized formulation showed a clear appearance (++), acceptable injectability (Pass), viscosity(151,798 mPa s), gelation temperature (36 °C), gelation time (213 s), preferable cell viability and cell proliferation, conformed to first-order release kinetics, and had a significant antibacterial effect. CONCLUSIONS The article demonstrates the great potential of the quercetin in-situ gel as an effective treatment for periodontitis.

BACKGROUND: Periodontitis is a severe chronic inflammatory disease, whose traditional systemic antimicrobial therapy faces great limitations. In-situ gels provide an effective solution as an emerging local drug delivery system. METHODS: In this study, the novel thermosensitive poloxamer/carbopol in-situ gels loaded with 20 lmol/L quercetin for the treatment of periodontitis were prepared by cold method. Thirteen batches of in-situ gels based on two independent factors (X1 : poloxamer 407 and X2 : carbopol 934P) were designed and optimized by the statistical method of central composite design (CCD). The transparency, pH, injectability, viscosity, gelation temperature, gelation time, elasticity modulus, degradation rate and in-vitro drug release studies of the batches were evaluated, and the percentage of drug release in the first hour, the time required for 90% drug release, gelation temperature, and gelation time were selected as dependent variables. RESULTS: These two independent factors significantly affected the four dependent variables (p < 0.05). The optimization result displayed that the optimized concentration of poloxamer 407 was 20.84% (w/v), and carbopol 934P was 0.5% (w/v). The optimized formulation showed a clear appearance (++), acceptable injectability (Pass), viscosity(151,798 mPa s), gelation temperature (36 °C), gelation time (213 s), preferable cell viability and cell proliferation, conformed to first-order release kinetics, and had a significant antibacterial effect. CONCLUSIONS The article demonstrates the great potential of the quercetin in-situ gel as an effective treatment for periodontitis.

BACKGROUND: Periodontitis is a severe chronic inflammatory disease, whose traditional systemic antimicrobial therapy faces great limitations. In-situ gels provide an effective solution as an emerging local drug delivery system. METHODS: In this study, the novel thermosensitive poloxamer/carbopol in-situ gels loaded with 20 lmol/L quercetin for the treatment of periodontitis were prepared by cold method. Thirteen batches of in-situ gels based on two independent factors (X1 : poloxamer 407 and X2 : carbopol 934P) were designed and optimized by the statistical method of central composite design (CCD). The transparency, pH, injectability, viscosity, gelation temperature, gelation time, elasticity modulus, degradation rate and in-vitro drug release studies of the batches were evaluated, and the percentage of drug release in the first hour, the time required for 90% drug release, gelation temperature, and gelation time were selected as dependent variables. RESULTS: These two independent factors significantly affected the four dependent variables (p < 0.05). The optimization result displayed that the optimized concentration of poloxamer 407 was 20.84% (w/v), and carbopol 934P was 0.5% (w/v). The optimized formulation showed a clear appearance (++), acceptable injectability (Pass), viscosity(151,798 mPa s), gelation temperature (36 °C), gelation time (213 s), preferable cell viability and cell proliferation, conformed to first-order release kinetics, and had a significant antibacterial effect. CONCLUSIONS The article demonstrates the great potential of the quercetin in-situ gel as an effective treatment for periodontitis.

BACKGROUND: Periodontitis is a severe chronic inflammatory disease, whose traditional systemic antimicrobial therapy faces great limitations. In-situ gels provide an effective solution as an emerging local drug delivery system. METHODS: In this study, the novel thermosensitive poloxamer/carbopol in-situ gels loaded with 20 lmol/L quercetin for the treatment of periodontitis were prepared by cold method. Thirteen batches of in-situ gels based on two independent factors (X1 : poloxamer 407 and X2 : carbopol 934P) were designed and optimized by the statistical method of central composite design (CCD). The transparency, pH, injectability, viscosity, gelation temperature, gelation time, elasticity modulus, degradation rate and in-vitro drug release studies of the batches were evaluated, and the percentage of drug release in the first hour, the time required for 90% drug release, gelation temperature, and gelation time were selected as dependent variables. RESULTS: These two independent factors significantly affected the four dependent variables (p < 0.05). The optimization result displayed that the optimized concentration of poloxamer 407 was 20.84% (w/v), and carbopol 934P was 0.5% (w/v). The optimized formulation showed a clear appearance (++), acceptable injectability (Pass), viscosity(151,798 mPa s), gelation temperature (36 °C), gelation time (213 s), preferable cell viability and cell proliferation, conformed to first-order release kinetics, and had a significant antibacterial effect. CONCLUSIONS The article demonstrates the great potential of the quercetin in-situ gel as an effective treatment for periodontitis.

BACKGROUND: Periodontitis is a severe chronic inflammatory disease, whose traditional systemic antimicrobial therapy faces great limitations. In-situ gels provide an effective solution as an emerging local drug delivery system. METHODS: In this study, the novel thermosensitive poloxamer/carbopol in-situ gels loaded with 20 lmol/L quercetin for the treatment of periodontitis were prepared by cold method. Thirteen batches of in-situ gels based on two independent factors (X1 : poloxamer 407 and X2 : carbopol 934P) were designed and optimized by the statistical method of central composite design (CCD). The transparency, pH, injectability, viscosity, gelation temperature, gelation time, elasticity modulus, degradation rate and in-vitro drug release studies of the batches were evaluated, and the percentage of drug release in the first hour, the time required for 90% drug release, gelation temperature, and gelation time were selected as dependent variables. RESULTS: These two independent factors significantly affected the four dependent variables (p < 0.05). The optimization result displayed that the optimized concentration of poloxamer 407 was 20.84% (w/v), and carbopol 934P was 0.5% (w/v). The optimized formulation showed a clear appearance (++), acceptable injectability (Pass), viscosity(151,798 mPa s), gelation temperature (36 °C), gelation time (213 s), preferable cell viability and cell proliferation, conformed to first-order release kinetics, and had a significant antibacterial effect. CONCLUSIONS The article demonstrates the great potential of the quercetin in-situ gel as an effective treatment for periodontitis.

Objective:To describe a prospective study of pre-operative tumor-bed boost performed at the 1.5 T MR-Linac in combination with adjuvant whole breast irradiation, and a first case, with an accentuation on clinical feasibility and safety.Methods:A phase II, single arm study recruiting early stage patients follows a paradigm that first boosts the tumor bed and then undergoes breast conservative surgery in 2 weeks, and last irradiates the whole breast in 6 weeks. The primary endpoint is ≥ grade 2 acute breast toxicity. A 43 years old patient affected by a breast carcinoma, not special type of the right-sided lateral quadrant, staged cT 2N 0M 0, was planned and treated. The dose, 8 Gy for one time, was calculated by Monaco on CT simulation images. Both the air electron stream effect (ESE) and the electron return effect (ERE) at the presence of 1.5 T magnetic field were evaluated. During the pre-treatment evaluation, we carried out adaptation-to-position adjustment. Results:The normal organ dosimetry is within toleration. The Dmax to the skin, the chin and the right upper arm was 8.44 Gy, 28.5 cGy and 17.8 cGy, respectively. There was no increased toxicity from ERE and ESE, and the treatment was well tolerated without > grade 1 acute toxicity. The patient received breast conservative surgery on day 7 without delayed wound healing.Conclusions:This is the first case successfully treated within a clinical trial by pre-operative tumor-bed boost under 1.5 T MR-Linac in our institution. More participants are needed to validate and optimize the paradigm.

Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and stable (MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68⁺ macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively, our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.

Objective:To investigate the radiation field and dose selection of patients with isolated chest wall recurrence (ICWR) after modified radical mastectomy, and analyze the prognostic factors related to subsequent chest wall recurrence.Methods:Clinical data of 201 patients with ICWR after mastectomy admitted to the Fifth Medical Center, Chinese PLA General Hospital from 1998 to 2018 were retrospectively analyzed. None of the patients received postoperative adjuvant radiotherapy. After ICWR, 48 patients (73.6%) underwent surgery and 155 patients (77.1%) received radiotherapy. Kaplan-Meier method was used to calculate the post-recurrence progression-free survival (PFS) rates and the difference was compared by log-rank test. Multivariate analysis was performed using Cox regression model. Competing risk model was adopted to estimate the subsequent local recurrence (sLR) rates after ICWR and the difference was compared with Gray test. Multivariate analysis was conducted using F&G analysis. Results:With a median follow up of 92.8 months after ICWR, the 5-year PFS rate was 23.2%, and the 5-year sLR rate was 35.7%. Multivariate analysis showed that patients with surgery plus radiotherapy and recurrence interval o F>12 months had a lower sLR rate. Patients with recurrence interval o F>48 months, local plus systemic treatment and surgery plus radiotherapy had a higher PFS rate. Among the 155 patients who received chest wall radiotherapy after ICWR, total chest wall irradiation plus local boost could improve the 5-year PFS rate compared with total chest wall irradiation alone (34.0% vs. 15.4%, P=0.004). Chest wall radiation dose (≤60 Gy vs.>60 Gy) exerted no significant effect upon the sLR and PFS rates (both P>0.05). In the 53 patients without surgery, the 5-year PFS rates were 9.1% and 20.5%( P=0.061) with tumor bed dose ≤60 Gy and>60 Gy, respectively. Conclusions:Local radiotherapy is recommended for patients with ICWR after modified radical mastectomy of breast cancer, including total chest wall radiation plus local boost. The radiation dose for recurrence should be increased to 60 Gy, and it should be above 60 Gy for those who have not undergone surgical resection. In addition, patients with ICWR still have a high risk of sLR, and more effective treatments need to be explored.

Objective:To analyze the prognosis of patients with isolated regional recurrence (RR) after mastectomy, and evaluate the efficacy of radiotherapy and identify the optimal radiation target volumes.Methods:Clinical data of 144 patients with first isolated RR after mastectomy between 2001 and 2018 were retrospectively analyzed. All patients had not received post-mastectomy radiotherapy. The primary endpoints consisted of the subsequent locoregional recurrence (sLRR), distant metastasis (DM), progression-free survival (PFS) and overall survival (OS).Results:With a median follow-up of 82.5 months after RR, the 5-year sLRR, DM, PFS and OS rates for the entire group were 42.1%, 71.9%, 22.9% and 62.6%, respectively. Local plus systemic therapy was an independent favorable prognostic factor for sLRR ( P<0.001) and PFS ( P=0.013). The sLRR rate in the surgery plus radiotherapy group was the lowest ( P<0.001). Surgery plus radiotherapy significantly reduced the 5-year risk of recurrence within the initially involved nodal regions ( P<0.001). Patients with chest wall irradiation obtained the 5-year subsequent chest wall recurrence rate of 12.1% compared to 14.8%( P=0.873) for those without chest wall irradiation. The subsequent supraclavicular recurrence rate was lower in patients with prophylactic supraclavicular irradiation than that without prophylactic supraclavicular irradiation (9.9% vs. 23.8%, P=0.206). The incidence rates of initially uninvolved axillary and internal mammary nodal recurrence were below 10% regardless of prophylactic irradiation or not. Conclusions:Patients with RR alone have an optimistic 5-year OS in the contemporary era. Comprehensive locoregional treatment including surgery and radiotherapy combined with systemic therapy is recommended. The chest wall, axillary and internal mammary nodal prophylactic irradiation should not be routinely performed for all patients with RR. The value of supraclavicular prophylactic irradiation remains to be evaluated.