Our Phase II investigation showed that NCT's morphological response is better evaluated at an earlier point in the process. STC15 Stage II/III rectal cancer patients, categorized as low- to intermediate-risk, can undergo considerable tumor reduction and reclassification following only four cycles of NCT treatment. The treatment's effects on tumor morphology are evident as early as two cycles. Nevertheless, the available data lacks a more nuanced stratification and evidence to substantiate pathological criteria. The objective of the current comparative study (COPEC trial) involving patients with II/III rectal cancer, categorized as low or intermediate risk, is twofold: to establish the pathological tumor regression grade (pTRG) rate following two or four cycles of neoadjuvant CAPOX therapy, and to ascertain the possibility of early detection of patients who may not respond to chemotherapy.
West China Hospital of Sichuan University's multicenter, prospective, non-inferior, randomized controlled trial (RCT) will encompass fourteen hospitals throughout China. Through the O-trial online system's (https://plus.o-trial.com/) central automated randomization process, eligible patients will be assigned to two or four cycles of CAPOX treatment in a 11:1 ratio. Total mesorectal excision is a viable option following two to four cycles of CAPOX treatment, with a dose of oxaliplatin at 130mg/m^2.
Every 21 days, a daily dose of 1000mg/m^2 capecitabine is given, initiating on day one.
Twice daily, on days one through fourteen, then, repeating every twenty-one days. The primary endpoint is the percentage of patients with pathological no-tumor regression (pTRG 3) measured post-surgery at each sub-center and confirmed by the principal center.
The COPEC trial aims to confirm that preoperative CAPOX chemotherapy, in low- and intermediate-risk stage II/III rectal cancer patients, yields a favorable response assessment after two cycles and quantifies the tumor pathological response rate following two cycles of CAPOX treatment. We anticipate the COPEC trial will contribute to establishing a standard consensus for low- and intermediate-risk rectal cancer, facilitating the early detection of stage II/III rectal patients with low- and intermediate risk who exhibit poor responses to NCT treatment.
ClinicalTrials.gov lists the study NCT04922853. The individual's registration occurred on June 4th, 2021.
The public can access details of the clinical trial NCT04922853 through ClinicalTrials.gov. It was on June 4, 2021, that the registration took place.
The simultaneous presence of lupus nephritis and lupus erythematosus tumidus (LET) as the very first indicators of systemic lupus erythematosus (SLE) represents a highly unusual, infrequent case. We detail a case of this nature, highlighting the diagnostic difficulties and therapeutic considerations arising from this rare combination.
A North African woman, aged 38, presented to the nephrology clinic with symptoms encompassing lower extremity swelling, fatigue, and a three-kilogram weight loss over a four-week period. The physical examination process detected LET lesions, specifically on the chest and neck. The laboratory findings demonstrated lymphopenia, decreased levels of C3 and C4 complement proteins, and the presence of antinuclear antibodies, anti-double-stranded DNA antibodies, and anti-SSA/Ro antibodies. Normal serum creatinine and nephrotic proteinuria were observed in the results of the renal function tests. Upon renal biopsy examination, Class V lupus nephritis was observed. Following a skin biopsy, the presence of lymphohistiocytic infiltrates and dermal mucin led to a conclusive LET diagnosis. RNA biomarker The patient was administered prednisone (1mg/kg/day) and hydroxychloroquine after being diagnosed with SLE using the 2019 EULAR/ACR criteria. Her cutaneous and renal symptoms demonstrated substantial improvement, as evidenced by the six-month and twelve-month follow-up assessments.
The uncommon simultaneous appearance of LET and lupus nephritis as the primary manifestation of SLE, particularly in North African populations, underscores the urgent need for more research to unravel the immunopathogenic pathways and prognostic factors of this connection.
The infrequent presentation of SLE with both LET and lupus nephritis as the initial symptoms, particularly in the North African population, demands further investigation into the associated immunopathogenic mechanisms and the predictive factors linked to this condition.
Immune checkpoint inhibitors (ICIs) often prove ineffective for treating estrogen receptor-positive (ER+) breast cancer, as the tumor microenvironment (TME) in these cancers is typically immunosuppressive and characterized by a low presence of tumor-infiltrating lymphocytes. Radiation therapy (RT) can potentially increase inflammation and lymphocyte infiltration within tumors, but does not result in enhanced responses to immunotherapies, like immune checkpoint inhibitors (ICIs), in these patients. One possible explanation for this consequence is the augmented influence of RT, which hinders anti-tumor immunity by inducing a rise in the presence of myeloid-derived suppressor cells and regulatory T cells within the tumor. We proposed that anti-estrogens, used as a standard treatment for ER+ breast cancer, could potentially reduce the adverse effects of radiation therapy. This reduction in effects was predicted to occur by decreasing the recruitment and activation of immune-suppressive cells in the irradiated tumor microenvironment, thus potentially improving anti-tumor immunity and the response to immunotherapeutic strategies.
In order to examine the effect of fulvestrant, a selective estrogen receptor downregulator, on the irradiated TME, unhampered by the concurrent growth inhibition of tumor cells by fulvestrant, we utilized the TC11 murine model of anti-estrogen resistant ER+ breast cancer. Immunocompetent syngeneic mice underwent orthotopic tumor transplantation. genetic syndrome Upon the establishment of tumors, fulvestrant or a control agent was administered, subsequently followed by external beam radiotherapy one week hence. Through the combined application of flow cytometry, microscopy, transcript level quantification, and cytokine profiling, we determined the number and functional state of immune cells present within the tumor. We evaluated the combined therapeutic effect of fulvestrant, radiation therapy, and immune checkpoint inhibitors on tumor response and animal survival.
Resistance to anti-estrogen therapy alone in TC11 tumors was overcome by fulvestrant, which slowed tumor regrowth following radiation therapy, and markedly modified multiple immune components within the irradiated tumor microenvironment. Fulvestrant reduced the influx of Ly6C+Ly6G+ cells, concurrently increasing markers indicative of pro-inflammatory myeloid cells and activated T cells, and subsequently increasing the ratio of CD8+ FOXP3+ T cells. Fulvestrant and radiotherapy (RT), when administered independently, had limited effects on tumor growth; in contrast, the combination of these treatments with immunotherapy checkpoint inhibitors (ICIs) resulted in a substantial decrease in tumor size and an increase in survival time.
Within a preclinical ER+ breast cancer model, the concurrent application of radiation therapy (RT) and fulvestrant can effectively overcome the tumor microenvironment's immunosuppressive nature, thereby strengthening the anti-tumor response and heightening the efficacy of immunotherapy, even in instances where tumor growth is no longer estrogen-dependent.
Fulvestrant, when administered alongside radiation therapy (RT), can conquer the immunosuppressive tumor microenvironment (TME) in a preclinical model of estrogen receptor-positive (ER+) breast cancer, enhancing the anti-tumor response and improving the response to immune checkpoint inhibitors (ICIs), even if the tumor's growth is no longer stimulated by estrogen.
A lowered production and activity of histone deacetylase (HDAC) 2 may potentially contribute to amplified inflammatory responses in patients with severe asthma. The connective tissue growth factor (CTGF) acts as a crucial mediator in the occurrence of airway fibrosis within severe asthma. Nevertheless, the function of the HDAC2/Sin3A/methyl-CpG-binding protein (MeCP) 2 corepressor complex in controlling CTGF production within lung fibroblasts continues to be elusive.
The research addressed the participation of the HDAC2/Sin3A/MeCP2 corepressor complex in endothelin (ET)-1's promotion of CTGF production within human lung fibroblasts (WI-38). Lung tissue from the ovalbumin-induced airway fibrosis model was analyzed for the expression of HDAC2, Sin3A, and MeCP2.
The expression of CTGF in WI-38 cells, stimulated by ET-1, was suppressed by the action of HDAC2. A time-dependent relationship between ET-1 treatment and its effects on HDAC2 activity and H3 acetylation was established, with a decrease in the former and an increase in the latter. Moreover, the elevated expression of HDAC2 prevented ET-1 from causing H3 acetylation. Pharmacological inhibition of c-Jun N-terminal kinase, extracellular signal-regulated kinase, or p38 pathways prevented ET-1 from inducing H3 acetylation by lowering HDAC2 phosphorylation and reducing the functionality of HDAC2. Both Sin3A and MeCP2 overexpression lessened the impact of ET-1 on CTGF expression and H3 acetylation. ET-1 triggered a disruption of the HDAC2/Sin3A/MeCP2 corepressor complex, causing HDAC2, Sin3A, and MeCP2 to detach from the CTGF promoter region. Increased levels of HDAC2, Sin3A, or MeCP2 suppressed the ET-1-mediated stimulation of AP-1-luciferase. The transfection of HDAC2 siRNA led to the reversal of Sin3A or MeCP2's suppression of ET-1-induced H3 acetylation and AP-1 luciferase activity. Ovalbumin-induced airway fibrosis displayed reduced protein levels of HDAC2 and Sin3A, contrasting with the consistent MeCP2 expression levels observed in the control group. The ratio of phospho-HDAC2 to HDAC2, along with H3 acetylation levels, were both higher in the lung tissue of this model in comparison to the control group. In human lung fibroblasts, the HDAC2/Sin3A/MeCP2 corepressor complex's regulation of H3 deacetylation within the CTGF promoter region directly suppresses CTGF expression, in the absence of any stimulation.