Case Report: Clinical benefit from multi-target tyrosine kinase inhibitor and PARP inhibitor in a patient with cancer of unknown primary with BRCA1 large genomic rearrangement

Background: Cancer of unknown primary (CUP), which accounts for 3%–5% of new cancer cases every year, involves the presence of a type of histologically confirmed metastatic tumors whose primary site cannot be confirmed by conventional diagnostic methods. This difficulty in identifying the primary site means that CUP patients fail to receive precisely targeted therapy. Most patients are treated with empiric chemotherapy, with a median survival of 6 months and even poorer prognosis within an unfavorable subset of CUP.Case report: An 80-year-old woman presented with masses in the abdomen. Following comprehensive imagological and immunohistochemical examinations, she was diagnosed with CUP. She emphatically declined chemotherapy; thus, anlotinib has been administered with patient consent since 02/07/2019, and stable disease (SD) was observed for 2 years. During subsequent treatment, a large genomic rearrangement in BRCA1 was identified in the patient via NGS, and SD was observed for a further 6 months following olaparib treatment. The type of LGR identified in this patient was discovered to be BRCA1 exon 17-18 inversion (inv), which has never been previously reported.Conclusion: For CUP patients, a chemo-free regimen seems to be acceptable as a first-line treatment, and NGS-guided targeted treatment could improve patient outcomes

Downregulation of hypoxia-inducible factor-1α by RNA interference alleviates the development of collagen-induced arthritis in rats

Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis. Hypoxia-inducible factor-1α (HIF-1α) as a transcription factor in response to hypoxia suggests that it could be a potential therapeutic target for the treatment of RA. In this study, we assessed whether the HIF pathway blockade attenuates the manifestations of RA in the collagen-induced arthritis (CIA) rat model. We constructed a short hairpin RNA (shRNA) lentiviral expression vector targeting HIF-1α (pLVX-shRNA-HIF-1α) and to achieve HIF-1α RNA interference. Quantitative RT-PCR, immunofluorescence staining, and western blot were used to detect the expressions of HIF-1α, vascular endothelial growth factor (VEGF), phsopho (p)-p65, and p-IКBɑ mRNA and protein, respectively. Micro-computed tomography was used to investigate joint morphology at different time points after CIA induction. Moreover, enzyme-linked immunosorbent assay (ELISA) was used to monitor the expression of inflammatory cytokines. In vitro analyses revealed that pLVX-shRNA-HIF-1α effectively inhibited the expression of HIF-1α and VEGF and led to the activation of p-65 and p-IКBɑ, as well as decreased proinflammatory cytokine expression in cell culture. Inhibition of HIF-1α in rats decreased signs of a systemic inflammatory condition, together with decreased pathological changes of RA. Moreover, downregulation of HIF-1α expression markedly reduced the synovitis and angiogenesis. In conclusion, we have shown that pharmacological inhibition of HIF-1 may improve the clinical manifestations of RA

Efficacy and safety of Jianpishengsui for chemotherapy-related fatigue in patients with non-small cell lung cancer : study protocol for a randomized placebo-controlled clinical trial

BACKGROUND: Chemotherapy-related fatigue (CRF) is a common symptom in non-small cell lung cancer (NSCLC) patients. A Chinese herbal formula cream for oral application, called Jianpishengsui (JPSS), is extensively used in the First Affiliated Hospital of Guangzhou University of Chinese Medicine as an internal preparation for CRF and is associated with a promising response. Due to the lack of high-quality clinical evidence, a randomized placebo-controlled trial is required to assess the efficacy and safety of JPSS. METHODS/DESIGN: The efficacy and safety of JPSS herbal formula cream will be evaluated through a prospective, randomized, placebo-controlled trial conducted in the First Affiliated Hospital of Guangzhou University of Chinese Medicine. NSCLC patients with CRF will be randomized into two groups at a ratio of 1:1. Each group will receive either 15 g of the oral JPSS herbal formula cream or placebo twice a day from day 6 to day 20 during two courses of paclitaxel + platinum/docetaxel + platinum/pemetrexed + platinum (TP/DP/AP) chemotherapy. The primary endpoint is the difference in the degree of fatigue between baseline (the day before the start of the intervention) and day 42, which will be assessed by the Revised Piper Fatigue Scale score. The secondary endpoints are quality of life (measured by the 43-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer C43), Eastern Cooperative Oncology Group Performance Status, and Traditional Chinese Medicine syndrome score. The toxicity of the treatments will also be evaluated at the same time. All outcomes will be measured at baseline, day 6, day 21, and day 42 of the treatment. DISCUSSION: This randomized trial will investigate the efficacy and safety of JPSS applied for CRF in patients with NSCLC. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900023451. Registered on 28 May 2019

Qu-Yu-Jie-Du Decoction Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Modulation of Neutrophils and Macrophage Infiltration

Background. Inflammatory bowel disease (IBD) is becoming a global disease. A percentage of IBD patients will not react to therapy or will lose their response. Qu-Yu-Jie-Du Decoction (QYJD) is a traditional Chinese medicine formula commonly used for intestinal diseases. It has been reported that QYJD has an anti-inflammatory effect, but the mechanism is not fully understood. In this study, we mainly evaluated the anti-inflammatory effect of QYJD and explored the possible mechanisms. Methods. Twenty-four BALB/c mice were randomly divided into 4 groups according to their body weight, namely, the control group, the dextran sulfate sodium (DSS) group, the DSS + QYJD group, and the QYJD group. Mice were given 3% DSS drinking water freely, and at the same time, mice were given normal saline or QYJD (4.44 mg/g/d), respectively. Mental state, faeces, and weight were recorded every day. On the 10th day, the mice were sacrificed and collected for investigation. The length of the mice colon was measured. Histological analysis was used to detect the morphological changes in the colon. Immunohistochemistry was used to measure the infiltration of macrophages (F4/80, CD163) and neutrophils (Ly6G). Colorimetry was used to detect the myeloperoxidase (MPO) activity of colon tissues. ELISA was utilized to detect associated inflammatory cytokines and chemokines in colon tissues. Results. QYJD alleviated the weight loss and colitis symptoms of mice caused by DSS. QYJD fought against the shortening of the intestine caused by DSS; that is, it improved the decline of intestinal compliance in mice and had a protective effect on colon tissues. The mechanisms were related to downregulating macrophages and neutrophils in colon tissues of infiltration. Besides, QYJD simultaneously reduced the activity of myeloperoxidase activity (MPO) and the contents of IL-1β, IL-6, TNF-α, TGF-β, CCL2, and CXCL2 in colon tissues. Conclusions. QYJD can ameliorate DSS-induced colitis in mice and the mechanism is connected with a reduction in neutrophil and macrophage infiltration

Vitamin E intake is inversely associated with NAFLD measured by liver ultrasound transient elastography

Abstract Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, whose severe form is associated with oxidative stress. Vitamin E as an antioxidant has a protective potential in NAFLD. Whether dietary intake of vitamin E, supplementary vitamin E use, and total vitamin E have a preventive effect on NAFLD requires investigation. A cross-sectional study used data from the National Health and Nutrition Examination Survey (2017–2020) was conducted. Vitamin E intake, including dietary vitamin E, supplementary vitamin E use, and total vitamin E, was obtained from the average of two 24-h dietary recall interviews. The extent of hepatic steatosis was measured by liver ultrasound transient elastography and presented as controlled attenuated parameter (CAP) scores. Participants were diagnosed with NAFLD based on CAP threshold values of 288 dB/m and 263 dB/m. The statistical software R and survey-weighted statistical models were used to examine the association between vitamin E intake and hepatic steatosis and NAFLD. Overall, 6122 participants were included for NAFLD analysis. After adjusting for age, gender, race, poverty level index, alcohol consumption, smoking status, vigorous recreational activity, body mass index, abdominal circumference, hyperlipidemia, hypertension, diabetes, and supplementary vitamin E use, dietary vitamin E was inversely associated with NAFLD. The corresponding odds ratios (OR) and 95% confidence intervals (CI) of NAFLD for dietary vitamin E intake as continuous and the highest quartile were 0.9592 (0.9340–0.9851, P = 0.0039) and 0.5983 (0.4136–0.8654, P = 0.0091) (P trend = 0.0056). Supplementary vitamin E was significantly inversely associated with NAFLD (fully adjusted model: OR = 0.6565 95% CI 0.4569–0.9432, P = 0.0249). A marginal improvement in total vitamin E for NAFLD was identified. The ORs (95% CIs, P) for the total vitamin E intake as continuous and the highest quartile in the fully adjusted model were 0.9669 (0.9471–0.9871, P = 0.0029) and 0.6743 (0.4515–1.0071, P = 0.0538). Sensitivity analysis indicated these findings were robust. The protective effects of vitamin E significantly differed in the stratum of hyperlipidemia (P interaction < 0.05). However, no statistically significant results were identified when the threshold value was set as 263 dB/m. Vitamin E intake, encompassing both dietary and supplemental forms, as well as total vitamin E intake, demonstrated a protective association with NAFLD. Augmenting dietary intake of vitamin E proves advantageous in the prevention of NAFLD, particularly among individuals devoid of hyperlipidemia

Chinese and Western Integrative Medicine for Stage IIIb-IVb Non-Small Cell Lung Cancer: Design and Rationale of a Multi-center, Prospective Registry (NSCLC-Chinese and Western Integrative Medicine cohort)

Introduction: This planned multicenter observational study will evaluate the overall survival of those undergoing integrated Chinese and Western medicine for stage IIIb-IVb non-small cell lung cancer and analyze the factors related to the prognosis. Method and Analysis: The prospective cohort will enroll patients with stage IIIb-IVb NSCLC from March 1, 2019, to December 31, 2025, and follow them for 5 years. We plan to collect data on the patients’ demographics, treatment, overall survival, and factors related to the prognosis. Ethics and Dissemination: The institutional review board and ethics committee reviewed the study protocol. All patients will provide informed consent before enrollment. Trial registration number: ChiCTR190002143

A cohort study to examine the use of Chinese herbal medicine in combination with conventional therapies for patients with hepatocellular carcinoma in China

Background: Hepatocellular carcinoma (HCC) is one of the major malignancies associated with high mortality rates. Chinese herbal medicine (CHM) alone, or in combination with conventional therapies (CT), has been widely used for patients with HCC in China. This study aims to explore how integrative therapy (IT) through the combination of CHM and CT affects the survival of patients with intermediate-advanced HCC. Methods: A retrospective cohort study was performed at the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China. Data of consecutive patients diagnosed with intermediate-advanced HCC and a specific traditional Chinese medicine diagnostic pattern between January 2006 and December 2013 were retrieved from the electronic medical record system at the hospital. Patients were divided into 3 groups based on the therapies used, that is, IT, CHM alone, and CT alone, and the survival times of these patients was compared. Results: A total of 328 patients were included in this study. Median follow-up period was 26.4 months (95% confidence interval [CI] = 22.7-38.9). Median overall survival was 11.0 months for IT, 8.6 months for CHM, and 9.4 months for CT groups (P < .001). The adjusted hazard ratio (HR) of death for the IT group was 0.55 (95% CI = 0.38-0.79, P = .001) relative to the CT group and 0.68 (95% CI = 0.52-0.90, P = .007) relative to the CHM group, after adjusting for the factors that impact prognosis. Stratified analysis shows that IT can significantly lower the risk of death, especially for patients with good performance status (PS) and Child-Pugh class A. Conclusions: It was indicated that the integrative approach with combination of CHM and CT might improve survival for patients with intermediate-advanced HCC, especially for patients with good PS and Child-Pugh class A. However, a randomized controlled trial is warranted for a conclusive statement

Repurposing of Pirfenidone (Anti-Pulmonary Fibrosis Drug) for Treatment of Rheumatoid Arthritis

Clinical studies have shown that pirfenidone (PFD) effectively relieves joint pain in rheumatoid arthritis (RA) patients. However, the detailed mechanisms underlying the anti-RA effects of PFD have not been investigated. This study was undertaken to investigate the repurposing of PFD for the treatment of RA, and explore its anti-rheumatic mechanisms. A collagen-induced arthritis (CIA) rat model was used to observe joint pathological changes following PFD treatment. Based on bioinformatics to predict the mechanism of PFD anti-RA, using EA. hy926 and TNF-α-induced MH7A cells to establish in vitro model to explore its biological mechanism from the perspectives of synovial inflammation and angiogenesis. PFD significantly relieved pathological changes, including joint swelling, synovial hyperplasia, inflammatory cell infiltration and joint destruction. PFD was also associated with reduced expression of MMP-3 and VEGF in articular chondrocytes and synovial cells of CIA rats (p < 0.05). Using bioinformatic methods, we predicted that PFD inhibits cell inflammation and migration by interfering with the JAK2/STAT3 and Akt pathways. These results were verified using in vitro models. In particular, PFD effectively reduced the expression of pro-inflammatory, chondrogenic, and angiogenic cytokines, such as IL-1β, IL-6, IL-8, MMP-1/3/2/9 and VEGF (p < 0.05), in TNF-α-induced MH7A cells. In addition, PFD significantly reduced the production of MMP-2/9 and VEGF in EA. hy926 cells, thereby weakening migration and inhibiting angiogenesis (p < 0.05). These findings suggest that PFD may alleviate the pathological process in CIA rats, by inhibiting inflammation and angiogenesis through multiple pathways, and serve as a potential therapeutic drug for RA.</p

A Three-Dimensional Co-Culture Model for Rheumatoid Arthritis Pannus Tissue

Three-dimensional (3D) co-culture models have closer physiological cell composition and behavior than traditional 2D culture. They exhibit pharmacological effects like in vivo responses, and therefore serve as a high-throughput drug screening model to evaluate drug efficacy and safety in vitro. In this study, we created a 3D co-culture environment to mimic pathological characteristics of rheumatoid arthritis (RA) pannus tissue. 3D scaffold was constructed by bioprinting technology with synovial fibroblasts (MH7A), vascular endothelial cells (EA.hy 926) and gelatin/alginate hydrogels. Cell viability was observed during 7-day culture and the proliferation rate of co-culture cells showed a stable increase stage. Cell-cell interactions were evaluated in the 3D printed scaffold and we found that spheroid size increased with time. TNF-α stimulated MH7A and EA.hy 926 in 3D pannus model showed higher vascular endothelial growth factor (VEGF) and angiopoietin (ANG) protein expression over time. For drug validation, methotrexate (MTX) was used to examine inhibition effects of angiogenesis in 3D pannus co-culture model. In conclusion, this 3D co-culture pannus model with biological characteristics may help the development of anti-RA drug research.</p

supplement_B_EDITS – Supplemental material for A Cohort Study to Examine the Use of Chinese Herbal Medicine in Combination With Conventional Therapies for Patients With Hepatocellular Carcinoma in China

<p>Supplemental material, supplement_B_EDITS for A Cohort Study to Examine the Use of Chinese Herbal Medicine in Combination With Conventional Therapies for Patients With Hepatocellular Carcinoma in China by Lingling Sun, Paul Fahey, Xiaoshu Zhu, Weng Ng, Zhuo Ping Chen, Yiwen Qiu, Hezheng Lai, Jietao Lin and Lizhu Lin in Integrative Cancer Therapies</p