Network Pharmacology Analysis on the Mechanism of Xihuangwan in Treating Rectal Cancer and Radiation Enteritis.

BACKGROUND: Recent studies have shown that XihuangWan (XHW) is a kind of Chinese medicine with significant anti-tumor and anti-inflammatory activities. However, its mechanism for preventing and treating radiation proctitis in rectal cancer patients during radiotherapy remains unclear. METHODS: This study employed the network pharmacology to establish a "drug-active ingredient-target genedisease" network via using TCMSP, SymMap, GeneCard, and OMIM databases. The PPI network was conducted by the String tool. The core targets of XHW in the treatment of rectal cancer and radiation enteritis were identified by topological analysis, and the functional annotation analysis and pathway enrichment analysis were performed. RESULTS: A total of 61 active ingredients of XHW ingredients, 4607 rectal cancer-related genes, 5803 radiation enteritis-related genes, and 68 common targets of XHW in the treatment of rectal cancer and radiation enteritis were obtained. PTGS1 and NR3C2, as identified potential targets, were significantly associated with OS of colorectal cancer patients. GO and KEGG enrichment analysis showed that bioinformatics annotation of these common genes was mainly involved in DNA-binding transcription factor, PI3K/Akt, TNF, HIF-1 signaling pathway, and colorectal cancer pathway. CONCLUSION: The active ingredients of XHW, mainly including Quercetin, Ellagic acid, and Stigmasterol, might act on common targets of rectal cancer and radiation enteritis, such as PTGS1, NR3C2, IL-6, EGFR, HIF-1A, CASP3, BCL2, ESR1, MYC, and PPARG, and regulate multiple signaling pathways like PI3K-Akt, TNF, and HIF-1 to inhibit tumor proliferation, tumor angiogenesis, inflammatory responses, and oxidative stress, thereby achieving prevention and treatment of radiation enteritis in rectal cancer patients during radiotherapy. It provided an important reference for further elucidating the anti-inflammation and anti-tumor mechanism and clinical application of XHW.

Coexistence of a novel SRBD1-ALK, ALK-CACNA1D double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report.

A Chinese male patient with advanced lung adenocarcinoma experienced disease progression one and a half years after receiving first-line immunochemotherapy. The second biopsy was performed and tissue immunohistochemistry revealed Anaplastic lymphoma kinase (ALK) expression in the cytoplasm of tumor cells, so he began to receive Alectinib treatment. Then the next generation sequencing found double fusion variants of S1 RNA binding domain 1 (SRBD1)- ALK and ALK- Calcium voltage-gated channel subunit alpha1 D (CACNA1D). After continuous Alectinib treatment for 7 months, almost complete response (CR) was achieved. The patient is currently taking Alectinib for 13 months, the condition is stable, and is waiting for the next cycle of efficacy evaluation.

A case report and literature review on respiratory failure with immune checkpoint inhibitors: a life-threatening adverse event.

Neuromuscular associated respiratory failure is a rare toxicity of immunotherapy for malignant tumors. In most cases, it may overlap with the symptoms of the primary disease or myocarditis, myositis and myasthenia gravis, resulting in difficult etiological diagnosis. Early detection and optimal treatment are still topics that need attention. Here, a case of 51-year-old male lung cancer patient with sintilimab-associated myasthenia gravis, myositis, and myocarditis overlap syndrome involving the diaphragm who developed severe type II respiratory failure was reported. After high-dose methylprednisolone, immunoglobulin and pyridostigmine intravenous injection with non-invasive positive pressure ventilation, the patient's symptoms improved significantly and was discharged. One year later, the patient received immunotherapy again due to tumor progression. After 53 days, he developed dyspnea again. Chest X-ray demonstrated marked elevation of the diaphragm, and the electromyogram demonstrated dysfunction of diaphragm. With rapid diagnosis and timely treatment, the patient was finally discharged safely. A comprehensive search of PubMed, EMBASE was performed to identify all previously reported cases of immune checkpoint inhibitors-associated respiratory failure. The potential mechanisms of respiratory failure caused by ICI-associated diaphragmatic dysfunction may be related to T cell-mediated immune disturbances and we proposed possible diagnostic processes. For patients with unexplained respiratory failure who are receiving immunotherapy, standardized diagnostic strategies should be implemented immediately on admission before deciding whether to conduct a more invasive diagnostic procedure or empirical treatment.

Successful management of Epstein­Barr virus­associated severe checkpoint inhibitor­related pneumonitis: A case report.

A novel current treatment, immunotherapy, is normally effective for pulmonary lymphoepithelial carcinoma (pLELC). However, it is frequently accompanied by responses such as immune checkpoint inhibitor-associated pneumonitis (CIP), a rare immune adverse reaction that may be fatal in severe cases. pLELC is known to be linked to Epstein-Barr virus (EBV), while associations between EBV and CIP in clinical settings have rarely been reported. A 57-year-old male patient with pLELC presented at our hospital with cough, expectoration, fever and dyspnea following his third course of immunotherapy at another hospital. Diagnosis of grade 4 CIP was confirmed. Simultaneously, a rapid increase in the EBV titer and response of CIP to corticosteroids were observed. The corticosteroids and antiviral drugs were then increased. In spite of his severe condition, the patient recovered within eight days. After discontinuing antiviral drugs, chest computed tomography indicated rapid lesion progression and significantly increased bilateral multiple metastases. To our knowledge, the present study was the first to report a case of CIP caused by EBV during immune checkpoint inhibitor treatment. It indicates that EBV may be associated with CIP development. As immunotherapy has off-target effects, clinicians should remain aware of combined corticosteroids and antivirals in similar cases.

A Risk-Scoring Model for Severe Checkpoint Inhibitor-Related Pneumonitis: A Case-Control Study.

BACKGROUND AND OBJECTIVE: Checkpoint inhibitor-related pneumonitis (CIP) is one of the most common serious and fatal adverse events associated with immune checkpoint inhibitors (ICIs). The study sought to identify risk factors of all-grade and severe CIP and to construct a risk-scoring model specifically for severe CIP. METHODS: This observational, retrospective case-control study involved 666 lung cancer patients who received ICIs between April 2018 and March 2021. The study analyzed patient demographic, preexisting lung diseases, and the characteristics and treatment of lung cancer to determine the risk factors for all-grade and severe CIP. A risk score for severe CIP was developed and validated in a separate patient cohort of 187 patients. RESULTS: Among 666 patients, 95 patients were afflicted with CIP, of which 37 were severe cases. Multivariate analysis revealed age ≥ 65 years, current smoking, chronic obstructive pulmonary disease, squamous cell carcinoma, prior thoracic radiotherapy, and extra-thoracic radiotherapy during ICI were independently associated with CIP events. Five factors, emphysema (odds ratio [OR] 2.87), interstitial lung disease (OR 4.76), pleural effusion (OR 3.00), history of radiotherapy during ICI (OR 4.30), and single-agent immunotherapy (OR 2.44) were independently associated with severe CIP and were incorporated into a risk-score model (score ranging 0-17). The area under the model receiver operating characteristic curve for the model was 0.769 in the development cohort and 0.749 in the validation cohort. CONCLUSIONS: The simple risk-scoring model may predict severe CIP in lung cancer patients receiving ICIs. For patients with high scores, clinicians should use ICIs with caution or strengthen the monitoring of these patients.

Case report: Spontaneous remission in lung carcinoma with a late relapse after adjuvant immunotherapy: Exceptional tumor micro-environment.

Spontaneous remission (SR) of local recurrence after adjuvant immunotherapy has rarely been reported, and the underlying mechanism is poorly understood. Herein, we reported a patient with stage cT2aN2M0 squamous cell lung carcinoma who received neoadjuvant and adjuvant treatment with nivolumab plus chemotherapy. The patient experienced a late relapse in the subcarinal lymph node seven months after the last dosage of treatment but achieved SR in the next three months without additional antitumor therapy. The complete response lasted for eleven months and counting. Notably, high copies of pathogenic microorganisms were detected in the patient's bronchoalveolar lavage fluid along with the recurrence but disappeared after SR. The patient also experienced a lymph node puncture-induced fever but had no other symptoms. A longitudinal analysis of infiltrated immune cells in the recurrent lymph node was performed by multiplex immunofluorescence and whole transcriptome sequencing, which revealed that CD8+ T cells were recruited during the initial relapse, specifically in the stromal area, then migrated into the tumor tissue, and continued to increase after elimination of tumor cells. Meanwhile, the initial recruitment of CD8+ T cells was coupled with a higher proportion of B cells, and the abundant neutrophil population was synchronous with the infiltration of CD8+ T cells into tumor cells. This is the first report on an Non-small cell lung cancer (NSCLC) patient with a late relapse after adjuvant immune checkpoint inhibitor (ICI) therapy who achieved SR. Our case highlights the complexity and plasticity of antitumor immunity and is expected to help find efficient strategies against the resistance of ICI treatment.

Univariable and Multivariable Two-Sample Mendelian Randomization Investigating the Effects of Leisure Sedentary Behaviors on the Risk of Lung Cancer.

Leisure sedentary behaviors (LSB) are widespread, and observational studies have provided emerging evidence that LSB play a role in the development of lung cancer (LC). However, the causal inference between LSB and LC remains unknown. Methods: We utilized univariable (UVMR) and multivariable two-sample Mendelian randomization (MVMR) analysis to disentangle the effects of LSB on the risk of LC. MR analysis was conducted with genetic variants from genome-wide association studies of LSB (408,815 persons from UK Biobank), containing 152 single-nucleotide polymorphisms (SNPs) for television (TV) watching, 37 SNPs for computer use, and four SNPs for driving, and LC from the International Lung Cancer Consortium (11,348 cases and 15,861 controls). Multiple sensitivity analyses were further performed to verify the causality. Results: UVMR demonstrated that genetically predisposed 1.5-h increase in LSB spent on watching TV increased the odds of LC by 90% [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.44-2.50; p < 0.001]. Similar trends were observed for squamous cell lung cancer (OR, 1.97; 95%CI, 1.31-2.94; p = 0.0010) and lung adenocarcinoma (OR, 1.64; 95%CI 1.12-2.39; p = 0.0110). The causal effects remained significant after adjusting for education (OR, 1.97; 95%CI, 1.44-2.68; p < 0.001) and body mass index (OR, 1.86; 95%CI, 1.36-2.54; p < 0.001) through MVMR approach. No association was found between prolonged LSB spent on computer use and driving and LC risk. Genetically predisposed prolonged LSB was additionally correlated with smoking (OR, 1.557; 95%CI, 1.287-1.884; p < 0.001) and alcohol consumption (OR, 1.010; 95%CI, 1.004-1.016; p = 0.0016). Consistency of results across complementary sensitivity MR methods further strengthened the causality. Conclusion: Robust evidence was demonstrated for an independent, causal effect of LSB spent on watching TV in increasing the risk of LC. Further work is necessary to investigate the potential mechanisms.

R-Phycoerythrin Induces SGC-7901 Apoptosis by Arresting Cell Cycle at S Phase.

R-Phycoerythrin (R-PE), one of the chemical constituents of red algae, could produce singlet oxygen upon excitation with the appropriate radiation and possibly be used in photodynamic therapy (PDT) for cancer. Documents reported that R-PE could inhibit cell proliferation in HepG2 and A549 cells, which was significative for cancer therapy. This is due to the fact that R-PE could kill cancer cells directly as well as by PDT. However, little is known about the cytotoxicity of R-PE to the SGC-7901 cell. In this study, it has been found that R-PE could inhibit SGC-7901 proliferation and induce cell apoptosis, which was achieved by arresting the SGC-7901 cell at S phase. CyclinA, CDK2 and CDC25A are proteins associated with the S phase, and it was found that R-PE could increase the expression of cyclin A protein and decrease the expression of CDK2 and CDC25A proteins. Thus, it was concluded that R-PE reduced the CDK2 protein activated through decreasing the CDC25A factor, which reduced the formation of Cyclin-CDK complex. The reduction of Cyclin-CDK complex made the SGC-7901 cells arrest at the S phase. Therefore, R-PE induced apoptosis by arresting the SGC-7901 cell at S phase was successful, which was achieved by the expression of the CDC25A protein, which reduced the CDK2 protein actived and the formation of Cyclin-CDK complex.

Increased HIV Testing among Men Who Have Sex with Men from 2008 to 2012, Nanjing, China.

BACKGROUND: HIV testing is the first point of HIV treatment entry for HIV-infected individuals and an avenue to engage persons at risk in prevention. In China, where the prevalence of HIV among men who have sex with men (MSM) has been rising over the last decade, uptake of HIV testing has been low. METHODS: We examined changes in HIV testing in the preceding 12 months through two cross-sectional surveys conducted among MSM in Nanjing, Jiangsu province, China in 2008 and 2012. Respondent-driven sampling (RDS) was used to recruit participants. Questionnaire interviews and venous blood were collected to measure HIV testing, risk behaviors, and prevalence of HIV, syphilis, and HSV-2. RESULTS: A total of 430 and 589 MSM were surveyed in 2008 and 2012, respectively, with comparable samples in each round with respect to demographic characteristics. HIV testing in the past 12 months increased significantly from 20.1% (95% CI 13.3-26.8) in 2008 to 46.0% (95% CI 39.3-51.4, p < 0.001) in 2012. HIV prevalence was stable, at 6.6% (95% CI 2.5-11.3) in 2008 and 10.1% (95% CI 6.6-13.9, p = 0.240) in 2012, as was syphilis (14.3% in 2008 vs. 9.9% in 2012, p = 0.240). HSV-2 prevalence (18.6% in 2008 vs. 10.2% in 2012, p = 0.040) and self-reported STI in the last year (24.3% in 2008 vs. 14.3% in 2012, p = 0.020) significantly decreased. Changes in reported sexual behaviors were mixed and the profiles of who did and did not test varied between 2008 and 2012. CONCLUSIONS: HIV testing uptake more than doubled among MSM in Nanjing from 2008 to 2012 -a period of massive promotion and scale up of testing programs for MSM. However, additional efforts are still needed to further increase the proportion of men being not only tested but also undergoing repeat testing if they engage in continued risk taking behavior.