Immune-related adverse events in non-small cell lung cancer: Occurrence, mechanisms and therapeutic strategies.

The emergence of immune checkpoint inhibitors (ICIs) has heralded a transformative era in the therapeutic landscape of non-small cell lung cancer (NSCLC). While ICIs have demonstrated clinical efficacy in a portion of patients with NSCLC, these treatments concurrently precipitate a spectrum of immune-related adverse events (irAEs), encompassing mild to severe manifestations, collectively posing a risk of significant organ damage. Consequently, there exists an imperative to augment our comprehension of the pathophysiological underpinnings of irAEs and to formulate more efficacious preventive and ameliorative strategies. In this comprehensive review, we delineate the clinical presentation of organ-specific irAEs in patients with NSCLC and provide an in-depth analysis of recent advancements in understanding the mechanisms driving ICI-induced toxicity. Furthermore, we discuss potential strategies and targets for ameliorating these irAEs. Ultimately, this review aims to furnish valuable insights to guide further research endeavours in the context of irAEs in NSCLC patients.

Multiple pulmonary cavernous haemangiomas with concurrent primary pulmonary adenocarcinoma: a case report and literature review.

Background: Cavernous haemangiomas (CHs) commonly occurred in the skin, subcutaneous tissue, muscles, and liver. Pulmonary cavernous haemangiomas (PCHs) are quite rare and usually present with nonspecific clinical symptoms. When lung cancer patients are complicated with pulmonary cavernous haemangiomas, radiologically, these haemangioma lesions can be easily misinterpreted as intrapulmonary metastases, potentially resulting in misdiagnosis, or missed diagnosis. Case presentation: The present study reported the case of a 53-year-old female patient with pulmonary adenocarcinoma coexisting with multiple PCHs. 18F-FDG-Positron emission tomography-computed tomography (PET-CT) showed an elevated glucose metabolism in the apicoposterior segment of the left upper lobe; however, the other nodules were not hypermetabolic. Percutaneous lung biopsy was performed on the nodule in the apicoposterior segment of the left upper lobe, which were diagnosed as primary adenocarcinoma. Some nodules in the upper left lobe underwent wedge resection by video-assisted thoracic surgery (VATS) and intraoperative frozen section identified as PCHs. Finally, the patient underwent lobectomy of the left upper lobe via VATS, cancerous nodule in the apicoposterior segment of the left upper lobe underwent genetic molecular testing of PCR-Sanger sequencing, suggested EGFR mutation, and patient received treatment with Osimertinib. During the 4-months follow-up, contrast-enhanced CT showed no recurrence of either disease. PCHs are rare benign tumours of the lung, which can lead to misdiagnosis due to their non-specific clinical symptoms and radiological features, especially when they coexist with lung cancer. PCHs is easily misunderstood as metastatic lung cancer, in this case, PET-CT can assist in differentiating benign from malignant. For the cases of early lung cancer complicated with PCHs, lung cancer can be surgically resected, and whether PCHs should be removed or not should be determined according to the size and distribution of the lesions.

Virtual Screening and Bioactivity Evaluation of Novel Androgen Receptor Antagonists From Anti-PCa Traditional Chinese Medicine Prescriptions.

Prostate cancer (PCa), a type of malignancy that arises in the prostate gland, is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient treatment. Androgen receptor (AR) signaling pathway is necessary in the pathogenesis of prostate cancer, and there is a heightened interest in finding novel AR antagonists that target AR and its regulatory pathways. In our search for novel androgen receptor antagonists, we focus on the Traditional Chinese Medicine (TCM), which has been used for thousands of years to prove effective in the treatment of cancer. In this study, we collected 653 traditional Chinese medicine prescriptions that have certain therapeutic effect to prostate cancer, including the prescriptions and even the folk prescriptions. After summarizing the frequency of herbs and gathering the natural products contained in these prescriptions, we built a natural products database to do computer-aided virtual screening and drug-like evaluation to find potential AR antagonists. Totally 25 compounds were submitted to experimental biological activity tests. Through the MTT cell proliferation experiment, 5 chemicals were found to inhibit the proliferation of LNCaP cells in a concentration-dependent manner. Especially, MoL_11 was found to have good antagonistic activity and significantly inhibit fluorescence enzyme activity by the AR reporter gene experiment. Finally, the molecular dynamics simulation method was used to study the interaction between the most active compound MoL_11 and the wild-type and F876L mutant androgen receptor (WT/F876L AR), and it was found that F876L AR could not cause resistance to MoL_11.

Structure-activity relationship analysis of 3-phenylpyrazole derivatives as androgen receptor antagonists.

Prostate cancer (PCa), an epithelial malignancy that occurs in the prostate, reminds the second leading cause of cancer-related incidence in men worldwidely. Androgen receptor antagonists are the main therapeutic strategy of PCa, which can block the binding of androgen to androgen receptors. However, the long-term treatment of marketed anti-androgens in patients can inevitably cause drug resistance problem. The research of searching for new drugs with novel skeleton is always on the way. Recently, a series of 3-phenylpyrazole derivatives were reported to antagonize the function of AR, but their efficiencies are not good enough and need to be improved. In this work, comparative molecular field analysis and comparative molecular similarity indices analysis methods were employed to study the structure activity relationships of these derivatives. Two different methods were used to obtain the optimal molecular conformation alignments, one is based on atomic alignment and the other is based on molecular docking. The final result shows that both these two strategies can obtain satisfactory results and the atomic alignment performs a little better than docking. The models illustrate the key structural features highly related with the androgenic bioactivity and provide valuable suggestions for the design of new androgen receptor antagonists in future.Communicated by Ramaswamy H. Sarma.

QSAR Analysis of a Series of Hydantoin-based Androgen Receptor Modulators and Corresponding Binding Affinities.

Androgen receptor (AR), a member of the nuclear hormone receptor superfamily of intracellular ligand-dependent transcription factors, plays an indispensable role in normal male development through the regulation of androgen through the binding with endogenous androgens. Inappropriate amounts of androgens have a severe adverse effect on men. Excessive androgen may contribute to accelerate prostatic hypertrophy, even prostate cancer, while the absence of androgen may result in reduced muscle mass and strength, decreased bone mass, low energy, diminished sexual function and an increased risk of osteoporosis and fracture. In these cases, androgen receptor modulators are important to maintain the normal biological function of AR. So androgen receptor modulators are necessary for human being to improve their happy life index. To explore the relationships between molecular structures and corresponding binding abilities to aid the new AR modulator design, multiple linear regressions (MLR) are employed to analyze a series of hydantoin analogues, which can bind to androgen receptor acting as AR modulators. The obtained optimum model presents wonderful reliabilities and strong predictive abilities with R2 =0.858, QLOO2 =0.822, QLMO2 =0.813, QF12 =0.840, QF22 =0.807, QF32 =0.814, CCC=0.893, respectively. The derived model can be used to predict the binding abilities of unknown chemicals and may help to design novel molecules with better AR affinity activity.

Dynamic Change of CD34 Level during the Survival Process of Narrow Pedicle Flap.

OBJECTIVE: To evaluate the dynamic change of CD34 level during the survival process of narrow pedicle flaps. METHODS: Twenty-five white pigs were randomly and equally divided into 5 experimental groups. Five different type of narrow pedicle with different length-to-width ratio were employed, and each type of narrow pedicle was covered with 5 different size random flaps and which was classified into A, B, C, D and E for 5 groups. Group A was control group. Each type narrow pedicle with 5 different skin flaps were implanted onto the back of the pigs along the midline of back with a reverse direction. A 0.3 cm×0.3 cm full thickness skin flap in the middle of distal segment was collected and on 3rd, 5th, 7th and 14th days of post-operation. The expression of CD34 was measured by immunohistochemistry and enzyme-linked immunosorbent (ELISA). RESULTS: Histological examination showed that with the increasing of length-to-width ratio of the narrow pedicle skin flaps, the expression of CD34 increased in the skin flaps. Increased level of CD34 was found on 3rd day post-operation, and the peak expression was found on 7th day. Persistent high level of CD34 was found until 14th day. CONCLUSION: Increased CD34 level in the distal skin flap, there is the association between CD34 level and ischemia injury. Moreover, CD34 expression plays an important role during the repair processes of pedicle flaps.

A method for reconstruction of vermilion tubercle.

BACKGROUND: This article reports on the bilateral lip mucosa flaps (BLMFs) for reconstruction of the vermilion tubercle of the corrected cleft lip deformity. METHODS: From 2005 to 2013, the bilateral mucosa flaps procedures were performed on 34 secondary cleft lip patients (bilateral, n = 25; unilateral, n = 9). We retrospectively reviewed the pre-, intra-, and postoperative data of these 34 cases receiving BLMFs. RESULTS: Satisfactory results were obtained, both cosmetically and functionally, in all 34 patients. Lateral projection measurements of the reconstructive vermilion tubercle showed a mean increase of 151%. There were minimal perioperative complications. The color and texture matched well with the surrounding tissue. The postoperative scars are not remarkable at all. CONCLUSIONS: The technique is relatively simple. The BLMFs provided a versatile and reliable option for the reconstruction of the vermilion tubercle from secondary cleft lip deformities.

Clinical features and expressions of Foxp3 and IL-17 in type 1 autoimmune pancreatitis in China.

BACKGROUND: Autoimmune pancreatitis (AIP) is a distinct type of pancreatitis associated with a presumed autoimmune mechanism. The aim of this study was to analyze the clinical features and expressions of forkhead box P3 (Foxp3) and interleukin-17 (IL-17) in type 1 AIP in China and to identify factors for differentiation of AIP from non-AIP chronic pancreatitis (CP). MATERIAL AND METHODS: We retrospectively reviewed pancreatic specimens with diagnosis of type 1 AIP and non-AIP CP at Sun Yat-Sen Memorial Hospital in China from January 2000 to December 2013. The clinical symptoms, serological data, imaging findings, histopathology, and immunohistochemical findings of Foxp3 and IL-17 in the 2 groups were analyzed. RESULTS: Twenty-nine patients with type 1 AIP and 20 patients with non-AIP CP were enrolled. Obstructive jaundice was more common in type 1 AIP than in non-AIP CP (62.1% vs. 30.0%, P=0.042). The diffuse or segmental enlargement of the pancreas was more frequent in type 1 AIP than in non-AIP CP (72.4% vs. 40.0%, P=0.038). Histopathology of type 1 AIP presented dense lymphoplasmacytic infiltration, "snowstorm-like" fibrosis and abundant immunoglobulin (Ig) G4+ cells. Foxp3+ cells were more frequently observed in type 1 AIP than in non-AIP CP. IL-17+ cell infiltration was similar between the 2 groups. Furthermore, a positive correlation was found between Foxp3+ and IgG4+ cell counts in the pancreas of patients with type 1 AIP. CONCLUSIONS: Type 1 AIP has distinctive symptoms, image, and pathological characteristics, which could be used for differentiation from non-AIP CP. Foxp3+ cells might be helpful to distinguish type 1 AIP from non-AIP CP.

Environmental risk assessment on capsaicin used as active substance for antifouling system on ships.

Biodegradation experiments were carried out with capsaicin to evaluate its degradability. The results show that capsaicin was readily biodegradable under aerobic conditions. The values of Kow and the calculated bioconcentration factor indicate that capsaicin have a low potential for bioconcentration. The fish acute toxicity tests conducted with Brachydanio rerio show LC50 for capsaicin was 5.98 mg L(-1). The tests of alga growth inhibition conducted with Selenastrum capricornutum suggest EC50 for capsaicin was 114 mg L(-1). The calculated PNEC (Predicted No Effect Concentration) was 4.9×10(-4) mg L(-1). The average PEC (Predicted Environmental Concentration) for OECD-EU commercial harbor and marina were 3.99×10(-6) and 2.49×10(-5) mg L(-1), respectively. These indicate that the PEC was much less than the PNEC for capsaicin. The low Kp value of capsaicin suggests the data about the risk of capsaicin to sediment organisms can be waived. According to the results from the analysis of the degradation, bioaccumulation, toxicity and accumulation in sediment, it can be concluded that capsaicin used as active substance for antifouling system on ships poses relatively low risk to marine environment.

[Application of slender narrow pedicle flap in facial skin cancer treatment].

OBJECTIVE: To introduce the application of slender narrow pedicle flap in repairing facial tissue defects after skin carcinoma excision, and investigate its survival mechanism. METHODS: The slender narrow pedicle iateral maxillocevical flap was designed with its pedicle including skin fascia or only the fascia located in front of auricle or behind of it, repaired 26 cases of facial defects, including 5 temporal skin basal cell carcinoma, 6 skin squamous cell carcinoma, and 1 facial skin malignant melanoma, 8 skin basal cell carcinoma, 5 skin squamous cell carcinoma, 1 skin mucinous carcinoma. In 26 cases, 24 cases their pedicles in front of the auricle, 2 cases behind of the auricle; 4 cases their pedicles only including fascia. The size of the flaps ranged from 3.0 cm x 2.5 cm to 10.0 cm x 8.0 cm. The width and length of the pedicle ranged 1.0-1.5 cm and 2-6 cm. RESULTS: 26 cases of the slender narrow pedicle flaps all survived and the results were satisfactory except 5 cases of distal congestion, then gradual recovery. CONCLUSIONS: This slender narrow flap don't include any major blood vessel, without dissecting the blood vessels in operating. Due to its slender pedicle, the whole flap looks like "pingpang bat", the flap rotation is easy and its coverage area is very large, without cat ears. The postoperative appearance (color, texture, cosmetic aspect) is satisfactory. This slender narrow flap is an extraordinary new flap design and is ideal for the repair of the facial tissue defect after skin carcinoma excision.

[Application of narrow hypodermal pedicled retroauricular flap in repairing preauricular soft tissue defect].

OBJECTIVE: To investigate the technique and effectiveness of using narrow hypodermal pedicled retroauricular flap for repairing preauricular soft tissue defect. METHODS: Between June 2008 and July 2011, 11 cases of preauricular soft tissue defect were treated, which were caused by resection of preauricular tumors, including 5 cases of pigmented nevus, 2 cases of basal cell carcinoma, 2 cases of mixed hemangioma, and 2 cases of skin papilloma. There were 7 males and 4 females, aged from 26 to 75 years (mean, 50 years). The disease duration was 3-50 years (mean, 35 years). The size of the soft tissue defect ranged from 1.5 cm x 1.0 cm to 3.5 cm x 3.0 cm. The narrow hypodermal pedicled retroauricular flap was designed with its pedicle along the pathway of the superficial temporal artery and posterior auricular artery through tunnel to repair the defects. The size of the flaps ranged from 1.8 cm x 1.3 cm to 3.8 cm x 3.3 cm with the pedicle of 2-5 cm in length and 0.4-0.7 cm in width. The donor site was sutured directly or repaired with local flap. RESULTS: All flaps survived and incisions healed primarily after operation. Eight cases were followed up 6 months to 1 year. The flaps had good texture, flexibility, and color, and the auricle appearance was satisfactory. No recurrence of tumor was found. CONCLUSION: The narrow hypodermal pedicled retroauricular flap has long and narrow pedicle, big transferring angle, large repairing area, no major blood vessel, and easy operation, so it is a simple and ideal technique for repairing preauricular soft tissue defect.

The application of bilateral lip mucosa flaps in repairing upper vermilion defects.

BACKGROUND: The lip is a primary aesthetic feature of the human face. Repair of vermilion defects represents a unique challenge to the reconstructive surgeon. The methods of repair are various and have both advantages and disadvantages. Bilateral lip mucosa flaps were applied to the repair of upper vermilion defects, and the effects were observed and reported in this article. METHODS: The bilateral lip mucosa flaps were designed. Two reverse triangular flaps were designed on both sides of the upper vermilion defect. These 2 flaps have the common pedicle in the vermilion depression site. Alternatively, a "λ" incision may be used in the wet vermilion. Then, the mucosa flaps were raised, and the dissection was performed between the orbicularis oris muscles and oral mucosa glands. Next, the bilateral mucosa flaps were rotated down 90° and inserted into the "λ" incision to increase the tissue volume of the middle upper lip and deepen the labiogingival sulcus. The common pedicle of the mucosa flaps was formed to the vermilion tubercle, and the incisions were sutured layer by layer. RESULTS: From 2005 to 2010, the bilateral mucosa flaps procedures were performed on 30 secondary cleft lip patients (bilateral, n=22; unilateral, n=8). Lateral projection measurements of the reconstructive vermilion tubercle showed a mean increase of 149%. Satisfactory results were obtained, both cosmetically and functionally, in all 30 patients. There were minimal perioperative complications. The postoperative scars are not remarkable at all. CONCLUSIONS: The technique is relatively simple. The bilateral lip mucosa flaps provided a versatile and reliable option for the correction of vermilion defects from secondary cleft lip deformities.

Spatial and vertical distribution of short chain chlorinated paraffins in soils from wastewater irrigated farmlands.

Chlorinated paraffins (CPs) are one of the most complex groups of halogenated contaminants in the environment. However, studies of short chain CPs (SCCPs) in China are very scarce. In this study, the concentrations and distribution of SCCPs in farm soils from a wastewater irrigated area in China were investigated. SCCPs were detected in all topsoil samples, with the sum of the concentrations (ΣSCCPs) in the range of 159.9-1450 ng/g (dry weight, dw). A noticeable spatial trend and specific congener distribution were observed in the wastewater irrigated farmland. Soil vertical profiles showed that ΣSCCP concentrations below the plowed layer decreased exponentially and had a significant positive relationship (R(2) > 0.83) with total organic carbon in soil cores. Furthermore, soil vertical distributions indicated that lower chlorinated (Cl(5-6)) and shorter chain (C(10-12)) congeners are more prone to migrate to deeper soil layers compared to highly chlorinated and longer chain congeners. This work demonstrated that effluents from sewage treatment plants (STPs) could be a significant source of SCCPs to the ambient environment and wastewater irrigation can lead to higher accumulation of SCCPs in farm soils.

Granular activated carbon adsorption and microwave regeneration for the treatment of 2,4,5-trichlorobiphenyl in simulated soil-washing solution.

The treatment of 2,4,5-trichlorobiphenyl (PCB29) in simulated soil-washing solution by granular activated carbon (GAC) adsorption and microwave (MW) regeneration was investigated in this study. The PCB29 adsorption process was carried out in a continuous flow adsorption column. After adsorption, the PCB29-loaded GAC was dried at 103 degrees C, and regenerated in a quartz reactor by 2450MHz MW irradiation at 700W for 5min. The efficacy of this procedure was analyzed by determining the rates and amounts of PCB29 adsorbed in successive adsorption/MW regeneration cycles. Effects of the regeneration on the textural properties and the PCB29 adsorption capacity of GAC were examined. It was found that after several adsorption/MW regeneration cycles, the adsorption rate of GAC increased, whereas, the adsorption capacity decreased, which could be explained according to the change of textural properties. Most of the PCB29 adsorbed on GAC was degraded within 3min under MW irradiation, and the analysis of degradation products by GC-MS demonstrated that PCB29 experienced dechlorination during this treatment.

Comparison of AC/O3-BAC and O3-BAC processes for removing organic pollutants in secondary effluent.

AC (activated carbon)/O3-BAC (biological activated carbon) process was employed to treat secondary effluent and compared to O3-BAC process. The effects of ozone dosages and empty bed contact time (EBCT) in BAC on dissolved organic carbon (DOC) removal were investigated. The results showed that the presence of AC improved ozone utilization and biodegradability of the effluent. DOC removal increased with ozone dosage and EBCT in BAC, however, 3 mg l(-1) ozone dosage with 15 min oxidation time and 15 min EBCT in BAC were more economical and efficient. For DOC removal, AC/O3-BAC was more efficient than O3-BAC and its synergetic effect was more than that in O3-BAC process. The biomass of the subsequent BAC unit in AC/O3-BAC process was more than that in O3-BAC process and much more than that in BAC alone. Except for organic pollutants with molecular weight (MW) >10 kDa, those of other MW range were decomposed much more by AC/O3 process than by O3 process. GC/MS analysis showed that dibutyl phthalate, bis(2-ethylhexyl) phthalate, 4-bromo-3-chloroaniline, 2-propanone-ethylhydrazone and phenol derivatives were prevalent organic compounds in the secondary effluent. Some aromatic compounds, such as 4-bromo-3-chloroaniline and 2,4-dichloro-benzenamine disappeared after AC/O3 treatment. However, some small molecules were generated, after further biological treatment by BAC, the kinds and concentration of organic compounds were greatly reduced.

[Photocatalytic degradation of DBPs in aqueous solutions].

Photocatalysis technology was used to investigate its removal capability of disinfection by products (DBPs). The photocatalytic degradation rates of different compounds were obviously larger than those in photolytic degradation. They were 3-7 times for halogenated alkyls and 2-3 times for alkenes and aromatic compounds. Investigation of photocatalytic degradation orderliness show that cinnamene > o-cresol > alkenes > alkyls.

[Prediction of photolysis half-lives of PCDD /Fs adsorbed on spruce needles optimized by genetic algorithm].

Adopting quantum chemical parameters of PCDD/Fs computed with quantum chemical PM3 algorithm, quantitative structure-property relationship (QSPR) model, which could predict photolysis half-life (t1/2) of PCDD/Fs adsorbed to spruce [Picea abies (L.) Karst.] needle surfaces, is established using genetic algorithm (GA) algorithm. It is considered that the main factors affecting lg t1/2 of PCDD/Fs are the energy of the highest occupied molecular orbital (EHOMO), ELUMO - EHOMO and average molecular polarizability (alpha). The lg t1/2 values increase with the increasing of EHOMO and a. The relationship between the lg t1/2 values and ELUMO - EHOMO is a parabolic curve. The lg t1/2 values increase with the increasing of ELUMO - EHOMO when ELUMO - EHOMO > or = 7.847 and decrease with the increasing of when ELUMO - EHOMO < or = 7.847.

Photocatalysis of p-chlorobenzoic acid in aqueous solution under irradiation of 254 nm and 185 nm UV light.

The photolytic and photocatalytic degradation of p-chlorobenzoic acid (p-CBA) in aqueous solution were investigated using two kinds of low-pressure mercury lamps: one emitted at 254 nm and the other emitted at 254 nm and 185 nm. Both the photolytic and photocatalytic degradations of p-CBA followed pseudo first-order reaction rate form. The rate constants decreased with increase of initial concentration in VUV and TiO2/VUV. The TiO2/VUV was the most efficient process, in which rate constants was 3.0-6.5 times as that in TiO2/UV depending on the initial concentration. The gas bubbling efficiently improved the mass transfer and the kind of bubbling gas had evident influence on the reaction rate except in UV photolysis. TOC reduction rate was greatly reduced in VUV and TiO2/VUV processes when bubbled with nitrogen gas, it was no more than one third of that when bubbled with oxygen, however, the degradation rate of p-CBA was not affected by bubbled nitrogen so greatly.

Photocatalytic oxidation and ozonation of catechol over carbon-black-modified nano-TiO2 thin films supported on Al sheet.

The photocatalytic activity of the carbon-black-modified nano-TiO2) (CB-TiO2) thin films was 1.5 times higher than that of TiO2 thin films in degrading Reactive Brilliant Red X-3B. Photocatalytic oxidation and ozonation of catechol over CB-TiO2 thin films supported on Al sheet was investigated. The experiments showed that ozone concentrations had an important effect on TOC removal. The combined photocatalysis with UV irradiation and ozonation (TiO2/UV/O3) process considerably increased TOC removal rate compared to combined photocatalysis with UV irradiation and oxygen oxidation (TiO2/UV/O2) process, ozonation alone (O3) process, combined ozonation and UV irradiation (UV/O3) process. The complete mineralization of catechol followed pseudo-zero-order kinetics dependent upon ozone (oxygen) concentration and indicated catechol concentration did not affect the kinetics during UV/O3 and TiO2/UV/O3 (O2) processes. The kinetic study showed that the rate constants in the complete mineralization of catechol with TiO2/UV/O3 are 1.32-1.80 times higher than that of UV/O3 with the same concentration of ozone. The rate constants are 2.56-5.36 times higher than the maximal rate constants of TiO2/UV/O2 and 4.68-9.8 times higher than the maximal rate constants of TiO2/UV.