UNASSIGNED: To evaluate VEGF-C-induced lymphoproliferation in conjunction with 5-fluorouracil (5-FU) antimetabolite treatment in a rabbit glaucoma filtration surgery (GFS) model.
UNASSIGNED: Thirty-two rabbits underwent GFS and were assigned to four groups (n = 8 each) defined by subconjunctival drug treatment: (a) VEGF-C combined with 5-FU, (b) 5-FU, (c) VEGF-C, (d) and control. Bleb survival, bleb measurements, and IOP were evaluated over 30 days. At the end, histology and anterior segment OCT were performed on some eyes. mRNA was isolated from the remaining eyes for RT-PCR evaluation of vessel-specific markers (lymphatics, podoplanin and LYVE-1; and blood vessels, CD31).
UNASSIGNED: Qualitatively and quantitatively, VEGF-C combined with 5-FU resulted in blebs which were posteriorly longer and wider than the other conditions: vs. 5-FU (P = 0.043 for longer, P = 0.046 for wider), vs. VEGF-C (P < 0.001, P < 0.001) and vs. control (P < 0.001, P < 0.001). After 30 days, the VEGF-C combined with 5-FU condition resulted in longer bleb survival compared with 5-FU (P = 0.025), VEGF-C (P < 0.001), and control (P < 0.001). Only the VEGF-C combined with 5-FU condition showed a negative correlation between IOP and time that was statistically significant (r = -0.533; P = 0.034). Anterior segment OCT and histology demonstrated larger blebs for the VEGF-C combined with 5-FU condition. Only conditions including VEGF-C led to increased expression of lymphatic markers (LYVE-1, P < 0.001-0.008 and podoplanin, P = 0.002-0.011). Expression of CD31 was not different between the groups (P = 0.978).
UNASSIGNED: Adding VEGF-C lymphoproliferation to standard antimetabolite treatment improved rabbit GFS success and may suggest a future strategy to improve human GFSs.

Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2α was identified via drug virtual screening through our analysis of ccRCC\'s protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients.

Tetrahymena are ciliated protists that have been used to study the effects of toxic chemicals, including anticancer drugs. In this study, we tested the inhibitory effects of six pyrimidine analogs (5-fluorouracil, floxuridine, 5\'-deoxy-5-fluorouridine, 5-fluorouridine, gemcitabine, and cytarabine) on wild-type CU428 and conditional mutant NP1 Tetrahymena thermophila at room temperature and the restrictive temperature (37°C) where NP1 does not form the oral apparatus. We found that phagocytosis was not required for pyrimidine analog entry and that all tested pyrimidine analogs inhibited growth except for cytarabine. IC50 values did not significantly differ between CU428 and NP1 for the same analog at either room temperature or 37°C. To investigate the mechanism of inhibition, we used two pyrimidine bases (uracil and thymine) and three nucleosides (uridine, thymidine, and 5-methyluridine) to determine whether the inhibitory effects from the pyrimidine analogs were reversible. We found that the inhibitory effects from 5-fluorouracil could be reversed by uracil and thymine, from floxuridine could be reversed by thymidine, and from 5\'-deoxy-5-fluorouridine could be reversed by uracil. None of the tested nucleobases or nucleosides could reverse the inhibitory effects of gemcitabine or 5-fluorouridine. Our results suggest that the five pyrimidine analogs act on different sites to inhibit T. thermophila growth and that nucleobases and nucleosides are metabolized differently in Tetrahymena.

BACKGROUND: Xanthoma disseminatum (XD) is a rare form of non-Langerhans histiocytosis with extensive cutaneous involvement. There is a paucity of evidence-based recommendations for treatment decision-making. Previous case reports have established purine analogues, especially cladribine, as a hopeful first-line treatment option, but characterization of the clinical and pathological responses is lacking.
OBJECTIVE: To characterize the clinical and pathological responses to cladribine monotherapy based on serial examinations in XD patients.
METHODS: We retrospectively studied the clinical, pathological and laboratory data in a cohort of five XD patients who received intravenous cladribine monotherapy with serial examinations in our hospital. Compared with baseline characteristics, changes in clinical features and pathological patterns were identified and analysed. We also conducted a literature review of reported cases of cladribine treatment in XD patients.
RESULTS: Four male and one female patient were involved in the study. All patients demonstrated satisfactory clinical responses to cladribine monotherapy after 5 to 10 cycles. We observed a pathological shift in pattern from classic xanthogranuloma to transitional fibrohistiocytic infiltration during the treatment, and pathological responses heralded persistent clinical improvement. Other than afebrile neutropenia, no prominent adverse events were identified. Sustainable lesion clearance was achieved in all five patients during the follow-up period, ranging from 19 to 66 months.
CONCLUSIONS: Cladribine monotherapy is an effective and well-tolerated therapeutic option for XD patients. Pathological transformation is a signature of the clinical response and possibly unveils the underlying histiocyte biology of diseases in the xanthogranuloma family.

Chemotherapy, the most widely accepted treatment for malignant tumors, is dependent on cell death induced by various drugs including antimetabolites, alkylating agents, mitotic spindle inhibitors, antitumor antibiotics, and hormonal anticancer drugs. In addition to causing side effects due to non-selective cytotoxicity, chemotherapeutic drugs can initiate and promote metastasis, which greatly reduces their clinical efficacy. The knowledge of how they induce metastasis is essential for developing strategies that improve the outcomes of chemotherapy. Herein, we summarize the recent findings on chemotherapy-induced metastasis and discuss the underlying mechanisms including tumor-initiating cell expansion, the epithelial-mesenchymal transition, extracellular vesicle involvement, and tumor microenvironment alterations. In addition, the use of combination treatments to overcome chemotherapy-induced metastasis is also elaborated.

Ginseng-containing traditional medicine preparations (G-TMPs) in combination with fluoropyrimidine-based chemotherapy (FBC) are well-known treatments for advanced gastric cancer (AGC), with a superior efficacy to FBC alone. However, evidence regarding their efficacy remains limited. The purpose of this meta-analysis is to evaluate the efficacy and safety of G-TMPs in combination with FBC for the treatment of AGC.
Eight electronic databases were searched for randomized controlled trials (RCTs) using G-TMPs with FBC for the treatment of AGC. The primary outcome included the tumor response, while the secondary outcomes included the quality of life (QoL), proportions of peripheral blood lymphocytes, adverse drug reactions (ADRs), and levels of cancer biomarkers. The quality of evidence for each outcome was assessed using GRADE profilers.
A total of 1,960 participants were involved in the 26 RCTs included. Patients treated with FBC plus G-TMPs had better objective response (risk ratio [RR] = 1.23, 95% confidence interval [CI]: 1.13 to 1.35, p < 0.00001) and disease control (RR = 1.13, 95% CI: 1.08 to 1.19, p < 0.00001) rates than those treated with FBC alone. Additionally, the combination group had a better QoL, higher proportions of CD3+ T cells, CD4+ T cells, and natural killer cells, as well as a higher CD4+/CD8+ T-cell ratio. Furthermore, lower levels of CA19-9, CA72-4, and CEA were confirmed in the combination treatment group. In addition, G-TMPs reduced the incidence of ADRs during chemotherapy.
In combination with FBC, G-TMPs can potentially enhance efficacy, reduce ADRs, and improve prognosis for patients with AGC. However, high-quality randomized studies remain warranted.
PROSPERO Number: CRD42021264938.

It is unclear whether the use of antineoplastic drugs for patients with lung cancer in China has changed after the implementation of the national drug price negotiation in 2016 and continual update of clinical guidelines. This study aims to evaluate the trends in antineoplastic drug use, cost and prescribing patterns among patients with lung cancer in major cities of China.
We conducted a retrospective observational study using data from January 2016 to December 2020.
This study used prescription records based on inpatient and outpatient hospital data from 97 hospitals in 9 major cities of China.
A total of 218 325 antineoplastic drug prescriptions in patients with lung cancer were retrospectively collected from the Hospital Prescription Analysis Cooperative Project during the study period.
Trends in antineoplastic drug use, cost and prescribing patterns among patients with lung cancer.
The yearly antineoplastic prescriptions increased by 85.6% from 28 594 in 2016 to 53 063 in 2020 (Z=1.71, p=0.086). Significant increases were seen in the prescriptions for protein kinase inhibitors (PKIs) and monoclonal antibodies (mAbs), whereas significant decreases were observed in antimetabolites, plant alkaloids and platinum compounds. The yearly cost increased progressively by 145.0% from ¥113.6 million in 2016 to ¥278.3 million in 2020 (Z=2.20, p=0.027). The top three anticancer drug classes in terms of total cost were PKIs, antimetabolites and mAbs. In prescribing patterns of antineoplastic agents for lung cancer, monotherapy, and triple or more drug combinations gradually increased, while dual combinations decreased significantly from 30.8% to 19.6%.
Prescription practices among patients with lung cancer in China underwent major changes during the study period. The observed trends can aid in understanding the present medication use status of patients with lung cancer in China and provide information for future drug management.

Fluoropyrimidine-based regimens have been investigated as the second line chemotherapy in patients with advanced pancreatic cancer refractory to gemcitabine. We conducted this systematic review and meta-analysis to evaluate the efficacy and safety profile of fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in such patients.
The databases of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ASCO Abstracts and ESMO Abstracts were systematically searched. Randomized controlled trials (RCTs) that compared fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer were included. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate (ORR) and serious toxicities. Statistical analyses were performed by using Review Manager 5.3. Egger\'s test was performed to assess the statistical evidence of publication bias by using stata 12.0.
A total of 1183 patients from six randomized controlled trials were included for this analysis. Fluoropyrimidine combination therapy increased ORR [RR 2.82 (1.83-4.33), p<0.00001] and PFS [HR 0.71 (0.62-0.82), p<0.00001], without significant heterogeneity. Fluoropyrimidine combination therapy improved OS [HR 0.82 (0.71-0.94), p = 0.006], with significant heterogeneity (I2 = 76%, p = 0.0009). The significant heterogeneity might have been caused by the different administration regimens and baseline characteristics. Peripheral neuropathy and diarrhea were more common in the regimens containing oxaliplatin and irinotecan, respectively. No publication bias was detected by Egger\'s tests.
Compared with fluoropyrimidine monotherapy, fluoropyrimidine combination therapy had a higher response rate and longer PFS in patients with gemcitabine-refractory advanced pancreatic cancer. Fluoropyrimidine combination therapy could be recommended in the second line setting. However, due to concerns about toxicities, the dose intensities of chemotherapy drugs should be carefully considered in patients with weakness.

To characterize and pharmacologically influence subconjunctival lymphatics in rabbit and mouse eyes.
Rabbits received subconjunctival injections of trypan blue or fixable fluorescent dextrans. Bleb-related outflow pathways were quantified. Immunofluorescence for vessel-specific markers (lymphatics [podoplanin and LYVE-1] and blood vessels [CD31]) were performed in native rabbit conjunctiva and after fixable fluorescent dextran injection. Vascular endothelial cell growth factor-C (VEGFC) was injected subconjunctivally in rabbits. mRNA and protein were assessed for the above markers using RT-PCR and Western blot. Alternatively, mouse studies used Prox1-tdTomato transgenic reporter mice. Subconjunctival injection conditions included: no injection, balanced salt solution (BSS), VEGFC, 5-fluorouracil (5FU) and two concentrations of mitomycin-C (MMC). Two mouse injection protocols (short and long) with different follow-up times and number of injections were performed. Mouse eyes were enucleated, flat mounts created, and subconjunctival branching and length assessed.
Rabbit eyes demonstrated clear bleb-related subconjunctival outflow pathways that were distinct from blood vessels and were without nasal/temporal predilection. Immunofluorescence against vessel-specific markers showed lymphatics and blood vessels in rabbit conjunctiva, and these lymphatics overlapped with bleb-related subconjunctival outflow pathways. Subconjunctival VEGFC increased lymphatic (P = 0.004-0.04) but not blood vessel (P = 0.77-0.84) mRNA or protein in rabbits. Prox1-tdTomato transgenic reporter mice demonstrated natively fluorescent lymphatics. Subconjunctival VEGFC increased murine lymphatic branching and length (P ≤ 0.001-0.004) while antimetabolites (P ≤ 0.001-0.043) did the opposite for the long protocol.
Subconjunctival lymphatics are pharmacologically responsive to both VEGFC and antimetabolites in two animal models studied using different methodologies. These results may be important for bleb-forming glaucoma surgeries or ocular drug delivery.

Purine, an abundant substrate in organisms, is a critical raw material for cell proliferation and an important factor for immune regulation. The purine de novo pathway and salvage pathway are tightly regulated by multiple enzymes, and dysfunction in these enzymes leads to excessive cell proliferation and immune imbalance that result in tumor progression. Maintaining the homeostasis of purine pools is an effective way to control cell growth and tumor evolution, and exploiting purine metabolism to suppress tumors suggests interesting directions for future research. In this review, we describe the process of purine metabolism and summarize the role and potential therapeutic effects of the major purine-metabolizing enzymes in ovarian cancer, including CD39, CD73, adenosine deaminase, adenylate kinase, hypoxanthine guanine phosphoribosyltransferase, inosine monophosphate dehydrogenase, purine nucleoside phosphorylase, dihydrofolate reductase and 5,10-methylenetetrahydrofolate reductase. Purinergic signaling is also described. We then provide an overview of the application of purine antimetabolites, comprising 6-thioguanine, 6-mercaptopurine, methotrexate, fludarabine and clopidogrel. Finally, we discuss the current challenges and future opportunities for targeting purine metabolism in the treatment-relevant cellular mechanisms of ovarian cancer.