Anus preservation in low rectal adenocarcinoma based on MMR/MSI status (APRAM): a study protocol for a randomised, controlled, open-label, multicentre phase III trial.

BACKGROUND: Anus preservation has been a challenge in the treatment of patients with low rectal adenocarcinoma (within 5 cm from the anal verge) because it is difficult to spare the anus with its functioning sphincter complex under the safe margin of tumour resection. Patients with dMMR/MSI-H can achieve a favourable complete response (CR) rate by using a single immune checkpoint inhibitor. For patients with pMMR/MSS/MSI-L, intensified neoadjuvant three-drug chemotherapy may be the preferred option for anal preservation. In addition, the watch and wait (W&W) strategy has been proven safe and feasible for patients with rectal cancer who achieve a clinical complete response (cCR). Therefore, we initiated this clinical trial to explore the optimal neoadjuvant treatment pattern for patients with low locally advanced rectal cancer (LARC) with different MMR/MSI statuses, aiming to achieve a higher cCR rate with the W&W strategy and ultimately provide more patients with a chance of anus preservation. METHODS: This is a randomised, controlled, open-label, multicentre phase III trial. Patients with clinical stage T2-4 and/or N + tumours located within 5 cm from the anal verge are considered eligible. Based on the results of pathological biopsy, the patients are divided into two groups: dMMR/MSI-H and pMMR/MSS. Patients in the dMMR/MSI-H group will be randomly allocated in a 1:1 ratio to either arm A (monoimmunotherapy) or arm B (short-course radiotherapy followed by monoimmunotherapy). Patients in the pMMR/MSS group will be initially treated with long-term pelvic radiation with concurrent capecitabine combined with irinotecan. Two weeks after the completion of chemoradiotherapy (CRT), the patients will be randomly allocated in a 1:1 ratio to arm C (XELIRI six cycle regime) or arm D (FOLFIRINOX nine cycle regime). The irinotecan dose will be adjusted according to the UGT1A1-genotype. After treatment, a comprehensive assessment will be performed to determine whether a cCR has been achieved. If achieved, the W&W strategy will be adopted; otherwise, total mesorectal excision (TME) will be performed. The primary endpoint is cCR with the maintenance of 12 months at least, determined using digital rectal examination, endoscopy, and rectal MRI or PET/CT as a supplementary method. DISCUSSION: APRAM will explore the best anus preservation model for low LARC, combining the strategies of consolidation chemotherapy, immunotherapy, and short-course radiotherapy, and aims to preserve the anus of more patients using W&W. Our study provides an accurate individual treatment mode based on the MMR/MSI status for patients with low LARC, and more patients will receive the opportunity for anus preservation under our therapeutic strategy, which would transform into long-term benefits. TRIAL REGISTRATION: Clinicaltrials.gov NCT05669092 (Registered 28th Nov 2022).

Lidocaine alleviates inflammation and pruritus in atopic dermatitis by blocking different population of sensory neurons.

BACKGROUND AND PURPOSE: Atopic dermatitis is a common chronic pruritic inflammatory disease of the skin involving neuro-immune communication. Neuronal mechanism-based therapeutic treatments remain lacking. We investigated the efficacy of intravenous lidocaine therapy on atopic dermatitis and the underlying neuro-immune mechanism. EXPERIMENTAL APPROACH: Pharmacological intervention, immunofluorescence, RNA-sequencing, genetic modification and immunoassay were performed to dissect the neuro-immune basis of itch and inflammation in atopic dermatitis-like mouse model and in patients. KEY RESULTS: Lidocaine alleviated skin lesions and itch in both atopic dermatitis patients and calcipotriol (MC903)-induced atopic dermatitis model by blocking subpopulation of sensory neurons. QX-314, a charged NaV blocker that enters through pathologically activated large-pore ion channels and selectivity inhibits a subpopulation of sensory neurons, has the same effects as lidocaine in atopic dermatitis model. Genetic silencing NaV 1.8-expressing sensory neurons was sufficient to restrict cutaneous inflammation and itch in the atopic dermatitis model. However, pharmacological blockade of TRPV1-positive nociceptors only abolished persistent itch but did not affect skin inflammation in the atopic dermatitis model, indicating a difference between sensory neuronal modulation of skin inflammation and itch. Inhibition of activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons by lidocaine largely accounts for the therapeutic effect of lidocaine in the atopic dermatitis model. CONCLUSION AND IMPLICATIONS: NaV 1.8+ sensory neurons play a critical role in pathogenesis of atopic dermatitis and lidocaine is a potential anti-inflammatory and anti-pruritic agent for atopic dermatitis. A dissociable difference for sensory neuronal modulation of skin inflammation and itch contributes to further understanding of pathogenesis in atopic dermatitis.

Salicylic Acid Enhances Heat Stress Resistance of Pleurotus ostreatus (Jacq.) P. Kumm through Metabolic Rearrangement.

Pleurotus ostreatus (Jacq.) P. Kumm is cultivated worldwide, and its growth is seriously threatened by heat stress. Here, we performed a comprehensive analysis to investigate the influence of the phytohormone salicylic acid (SA) in P. ostreatus under HS. The results showed that the hyphal growth recovery rate and the antioxidant capacity of P. ostreatus increased with exogenous SA application (0.01 mmol/L and 0.05 mmol/L) after HS treatment. Metabolomic and transcriptomic analyses showed that SA application (0.05 mmol/L) weakened central carbon metabolism to allow cells to survive HS efficiently. In addition, SA shifted glycolysis to one-carbon metabolism to produce ROS scavengers (GSH and NADPH) and reduced ROS production by altering mitochondrial metabolism. SA also maintained nucleotide homeostasis, led to membrane lipid remodeling, activated the MAPK pathway, and promoted the synthesis of cell-wall components. This study provides a reference for further study of SA in microorganisms.

Diterpenoids of macromycetes.

This review surveys the chemical and biological literature dealing with the isolation, structure elucidation and bioactivity of diterpenoids from the fruiting bodies of macromycetes, concentrating on work that has appeared in the literature up to December 2007. In addition, this paper examines the research of diterpenoids produced by macromycetes grown in mycelial culture and the culture conditions for the fermentation of macromycetes.

Activity of armillarisin B in vitro against plant pathogenic fungi.

The methanolic extract of the fruiting bodies of the mushroom Armillariella tabescens was found to show antifungal activity against Gibberella zeae. The active compound was isolated from the fruiting bodies of A. tabescens by bioassay-guided fractionation of the extract and identified as armillarisin B. Armillarisin B eventually corresponds to 2-hydroxy-2-phenylpropanediamide and its structure was confirmed on the basis of spectroscopic studies including 2D NMR experiments.

Physicochemical properties and bioactivities of original and Se-enriched polysaccharides with different molecular weights extracted from Pleurotus ostreatus.

Three polysaccharides (WZP1, WZP2, WZP3) and their Se-enriched products (SeWZP1, SeWZP2 and SeWZP3) were obtained from Pleurotus ostreatus using a simple, rapid method and HNO3-Na2SeO3 method, respectively. The molecular weight distribution profiles of all samples except SeWZP2 showed double peaks. The average molecular weights (Mw) of WZP1-3 were 48.6 kDa, 20.2 kDa and 11.8 kDa, respectively, and of SeWZP1-3 were 19.6 kDa, 37.7 kDa, 14.5 kDa, respectively. The complexity of monosaccharide composition of WZP1-3 was inversely proportional to the ethanol concentration used in the ethanol precipitation process. Additionally, the results of biological activity tests indicated that α-glucosidase inhibitory activity of WZP1-3 was related to the molecular weight and the monosaccharide composition complexity. The selenized modification can improve the α-glucosidase-inhibiting, hydroxyl radical-scavenging activity of P. ostreatus polysaccharides. Therefore, by improving their bioactivities by selenization, the polysaccharides of P. ostreatus could be utilized as a natural health food supplement.

[Effect of jingui shenqi pill on morphology of injured spinal cell apoptosis in rats caused by brachytherapy].

OBJECTIVE: To study the effect of Jingui Shenqi Pill (JSP) on morphology of spinal cell apoptosis in rats injured by 192Ir irradiation. METHODS: One hundred and twenty rats were randomly divided into four groups: the model group, the JSP group, the prednisone group and the normal group. Corresponding pharmaceutics were given to rats once a day for 14 days respectively. Then except rats in the normal group, the others received 192Ir interstitial irradiation with the dosage of 22 Gy using back-fixing technology. The injured segments of spinal cord were taken out for HE staining, TUNEL examination and observation with electron microscope 8 hrs, 24 hrs and 4 weeks after irradiation. RESULTS: HE staining examination showed no obvious histological change in rats 8 and 24 hrs after irradiation, but pathological changes, as tissue rarefaction and hemorrhage did found in white matter of spinal cord shown by TUNEL 4 weeks later. Electron microscopic examination and TUNEL staining showed that as compared with the model group, the apoptotic index in the JSP and predinisone treated groups was significantly lower (P < 0.01) 8 hrs after radiation, but it showed insignificant difference between groups at the time points of 24 hrs and 4 weeks after radiation (P > 0.05). CONCLUSION: JSP could act against apoptosis of gliocyte in spinal cord of rats in early stage after brachytherapy, indicating that JSP possessing a prednisone-like action.

A research on the relationship between ejaculation and serum testosterone level in men.

The purpose of this study is to gain understanding of the relationship between ejaculation and serum testosterone level in men. The serum testosterone concentrations of 28 volunteers were investigated daily during abstinence periods after ejaculation for two phases. The authors found that the fluctuations of testosterone levels from the 2nd to 5th day of abstinence were minimal. On the 7th day of abstinence, however, a clear peak of serum testosterone appeared, reaching 145.7% of the baseline ( P < 0.01). No regular fluctuation was observed following continuous abstinence after the peak. Ejaculation is the precondition and beginning of the special periodic serum testosterone level variations, which would not occur without ejaculation. The results showed that ejaculation-caused variations were characterized by a peak on the 7th day of abstinence; and that the effective time of an ejaculation is 7 days minimum. These data are the first to document the phenomenon of the periodic change in serum testosterone level; the correlation between ejaculation and periodic change in the serum testosterone level, and the pattern and characteristics of the periodic change.

Lycorine: a potential broad-spectrum agent against crop pathogenic fungi.

A screening test showed that lycorine exhibited significant antifungal activity against 24 pathogenic crop fungi at concentrations of 500 µg/ml and 100 µg/ml, respectively. Fusarium graminearum was selected for antifungal mechanism studies by observing its mycelial morphology and investigating the variations in its conductivity. In addition, the substance absorption and metabolism of F. graminearum were explored. The mechanism was revealed as being one by which lycorine destroyed the cellular membrane and further influenced substance absorption and cell metabolism.

[Comparisons of different methods for virus-elimination of edible fungi].

Four dsRNA bands were extracted from Pleurotus ostreatus TD300 by the dsRNA isolation technique with sizes of 8.2 kb, 2.5 kb, 2.1 kb, and 1.1 kb, respectively. Four virus-eliminated methods, i. e. hyphal tips cut (HTC), protoplast regeneration (PR), single spore hybridization (SSH), and frozen and lyophilized (FL), were applied to prepare virus-eliminated strains, and one virus-eliminated strain was selected for each virus-elimination method. The virus-eliminated strains were named as HTC8, PR15, FL01, and SSH11, respectively. There were low concentration of 8.2 kb dsRNA remained in HTC8, as well as low concentration of 8.2 kb and 2.5 kb dsRNA remained in FL01. However, no dsRNA remained in PR15 and SSH11. The hyphal growth rate and laccase activity of the virus-eliminated strains increased, especially HTC8 and PR15, whose hyphal growth rate was higher by 22.73% and 18.18%, and laccase activities higher by 145.83% and 134.38% than that of the original strain, respectively. The conclusion is that hyphal tips cut and protoplast regeneration are suitable to prepare virus-eliminated strains of edible fungi.