Dual­directional effect of vinorelbine combined with cisplatin or fluorouracil on tumor growth and metastasis in metronomic chemotherapy in breast cancer.

Metronomic chemotherapy (MCT) regimens may be associated with risks to the patient due to the ambiguity surrounding low dosages and schedules. In the present study, metronomic regimens of vinorelbine (NVB) combined with cisplatin (CDDP) or fluorouracil (5­FU) were chosen to study the dose­response associations with tumor growth and metastasis, along with the underlying mechanisms in angiogenesis, apoptosis and tumor immunity, using experimental techniques such as immunofluorescence, immunohistochemistry, western blotting and flow cytometry. The results demonstrated a dual­directional pharmacological action of promoting and suppressing tumor growth or metastasis in BALB/c mice bearing a 4T1 tumor at certain low and high doses of the drugs. Low doses of NVB combined with CDDP or 5­FU accelerated tumor growth by enhancing angiogenesis, increasing the expression of angiogenic proteins, NF­κB and osteopontin in tumor tissues, and inducing the accumulation of myeloid­derived suppressor cells and macrophages. By contrast, higher doses inhibited tumor growth by suppressing these effects. Notably, the upregulation of apoptotic proteins was observed after low­ and high­dose treatments. Furthermore, at low concentrations, NVB combined with CDDP or 5­FU stimulated certain functions of endothelial and tumor cells, including migration and invasion, whereas at higher concentrations they suppressed proliferation and induced apoptosis. Therefore, the results of the present study suggested the potential risks of metronomic combination chemotherapy by demonstrating that, at certain low doses, tumor growth or metastasis was promoted, and emphasized the existence of an effective dose interval that changes with different drug combinations. However, further studies are needed before a specific metronomic combination regimen can be administered clinically for cancer treatment.

Low-dose Cisplatin Induces Tumor Growth via Mobilization of Proangiogenic Bone Marrow-derived Cells in Mouse Models.

BACKGROUND/AIM: It is generally accepted that low-dose metronomic (LDM) chemotherapy mostly exerts its antitumor effects by inhibiting tumor angiogenesis. However, there is some evidence that LDM chemotherapy subsequently promotes tumor angiogenesis under certain regimens in animal models. The mechanisms responsible for these contradictory results are unclear. MATERIALS AND METHODS: Cisplatin (CDDP) was intraperitoneally administered to tumor-bearing mice at doses of 0.05-3 mg/kg every other day. The effects of LDM chemotherapy with CDDP on tumor growth and angiogenesis were observed. To determine the involved mechanisms, we analyzed the expression of vascular basement membrane proteins, transcription of angiogenesis-related genes in tumor tissues, and mobilization of proangiogenic bone marrow-derived cells (BMDCs) in circulating blood. RESULTS: The mean tumor weight with the 3 mg/kg q.o.d. regimen CDDP was significantly lower (by 57.3%) in the CDDP than in the control group. However, the tumor weight was 52.1% higher for the 0.19 mg/kg q.o.d. regimen in the CDDP group, which could be antagonized using 30 mg/kg all-trans retinoic acid. For the 0.19 mg/kg q.o.d., more tumor vascular structures were observed in the CDDP than in the control group (47.9±5.0 vs. 22.3±0.8, p<0.001). The mobilization of VEGFR2+ BMDCs and the mRNA expression of the proangiogenic genes MMP9, VEGFR1, VEGFR2 and VE-cadherin were increased in the 0.19 mg/kg regimen. CONCLUSION: These results indicate that metronomic CDDP promoted tumor angiogenesis and tumor growth via increased mobilization of proangiogenic BMDCs at certain low doses. This implies a potential therapeutic risk from an inappropriate LDM chemotherapy dosage and suggests that optimizing the LDM chemotherapy regimen is urgently needed.

Prehabilitation Before Gastrointestinal Cancer Surgery: Protocol for an Implementation Study.

BACKGROUND: Surgery remains the standard curative treatment for early-stage colorectal and upper gastrointestinal cancer. Reduced preoperative functional capacity, nutritional status, and psychological well-being are associated with poor postoperative outcomes. Prehabilitation aims to improve preoperative functional reserves through physical, nutritional, and psychological interventions. Yet, how it transitions from a trial setting to being integrated into a real-world health setting is unknown. OBJECTIVE: The primary aim is to evaluate the implementation of a multimodal (supervised exercise, nutrition, and nursing support) prehabilitation program into standard care for patients with gastrointestinal cancer (colorectal and upper gastrointestinal cancer) scheduled for curative intent surgery. The secondary aim is to determine the impact of a multimodal prehabilitation program on functional capacity, nutritional and psychological status, and surgical outcomes. METHODS: This is an implementation study that will investigate a multimodal prehabilitation intervention, in a nonblinded, nonrandomized, single-group, pre-post design. Patients diagnosed with colorectal and upper gastrointestinal cancer scheduled for potentially curative intent surgery at Concord Repatriation General Hospital, with ≥14 intervention days prior to surgery and are medically cleared to exercise will be eligible. The study will be evaluated using the Reach, Effectiveness, Adoption, Implementation, and Maintenance Evaluation Framework. RESULTS: The protocol was approved in December 2019 by the Concord Repatriation General Hospital Human Research Ethics Committee (reference number 2019/PID13679). Recruitment commenced in January 2020. In response to the COVID-19 pandemic, recruitment was paused in March 2020 and reopened in August 2020 with remote or telehealth intervention adaptations. Recruitment ended on December 31, 2021. Over the 16-month recruitment period, a total of 77 participants were recruited. CONCLUSIONS: Prehabilitation represents an opportunity to maximize functional capacity and improve surgical outcomes. The study will provide guidance and contribute to the evidence on the integration of prehabilitation into standard care using adaptive models of health care delivery including telehealth. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTR 12620000409976; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378974&isReview=true. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/41101.

Short-term multimodal prehabilitation improves functional capacity for colorectal cancer patients prior to surgery.

AIM: Evaluate feasibility and outcomes of a multimodal prehabiliation program in patients with stage I-III colorectal cancer (CRC) awaiting surgery. METHODS: Patients scheduled for elective CRC resection at Concord Repatriation General Hospital were recruited from pre-admission clinic between January and November 2018. Participants received a 2-4 week prehabilitation program consisting of supervised exercise sessions, nurse-led phone support, and written nutritional information. Participants were assessed at baseline, pre-surgery, and 4 weeks post-surgery. RESULTS: Twenty-two patients participated in the program: 55% male; median age 73 (56-86) years. Six (28%) required an interpreter. At baseline, 19 of 22 (86%) had at least one comorbidity. Median intervention length was 11.5 days (range 7-29). Participants attended 79% of scheduled exercise sessions (range 33-100%, mean 3.5 sessions) and 66% of nurse support calls (range 0-100%, mean 2.6 sessions). Between baseline and pre-surgery, participants reported increasing mean unsupervised moderate-intensity aerobic exercise from 17 (range 0-210) to 73 minutes/week (range 0-276) and mean vigorous-intensity aerobic exercise from 0 to 24 minutes/week (range 0-300). Resistance exercise sessions increased from 0.6 to 2.6 times/week. Mean 6-minute walk test distance increased by 48 meters (435-483 m) and 30-second "sit to stand" by 1.6 repetitions. Small improvements were seen in global quality of life and fatigue. Nutritional status and body composition remained unchanged. All participants were satisfied/strongly satisfied with the program and would recommend it to others. CONCLUSION: Our multimodal prehabilitation program was feasible in CRC patients inclusive of those from non-English speaking backgrounds, with improvement in functional capacity before CRC surgery.

Simple inorganic base promoted C-N and C-C formation: synthesis of benzo[4,5]imidazo[1,2-a]pyridines as functional AIEgens used for detecting picric acid.

Metal-free catalyzed intermolecular tandem Michael addition/cyclization has been developed for the synthesis of benzo[4,5]imidazo[1,2-a]pyridines from α-bromocinnamaldehyde and 2-substituted benzimidazoles. The reaction promoted by a simple inorganic base displays moderate to good yields and good functional group tolerance. The optical properties of some typical products have been investigated. We found that, due to the presence of the benzene ring at the C1-position of benzo[4,5]imidazo[1,2-a]pyridines which restricts intramolecular motion, as a new type of aggregation-induced emission (AIE) luminogen (AIEgen), they show very good solid-state fluorescence with quantum yields up to 88.80%. Importantly, the AIE performance of compound 3b can be useful to detect the nitroaromatic explosive picric acid (PA) with a detection limit and quenching constant of 42.5 nM and 7.27 × 104 M-M, respectively.

A New Co-Substitution Strategy as a Model to Study a Rare-Earth-Free Spinel-Type Phosphor with Red Emissions and Its Application in Light-Emitting Diodes.

The substitution of metal sites in Mg2TiO4 substrate leads to charge imbalance that will be closely related to a variety of changes including lattice structure, cell distortion, and photophysical properties. Herein, the co-substitution strategy of [Ga3+-Ga3+] for [Mg2+-Ti4+] and Sn4+ for Ti4+ achieves for the first time the novel Mg3Ga2SnO8 (MGS):xMn4+ (x = 0-3%) phosphors with efficient red emissions. In terms of X-ray powder diffraction (XRD) and Rietveld refinement analysis, MGS:Mn4+ possesses a structure isotypic of Mg2TiO4 in the cubic space group Fd3̅m (227). There are two types of octahedra for Mn4+ ions in this structure, where Ga3+ ions completely occupy a group of octahedral sites and Mg2+/Sn4+ has been randomly distributed over another group of octahedral sites. A strong excitation band in the broad spectral range (220-550 nm) has been identified, thus facilitating the commercial uses for blue LED chips excitation. An intense red emission band at 680 nm has been observed due to the characteristic 2Eg-4A2g transition of Mn4+ ions. A concentration quenching effect occurs when the Mn4+ content exceeds 1.5%, and the quenching mechanism is demonstrated to be dipole-quadrupole interactions. Temperature-dependent luminescence measurements support its good thermal stability, and the corresponding activation energy Ea is determined to be 0.2552 eV. The possible luminous mechanism of the Mn4+ ion is explained by the Tanabe-Sugano energy level diagram. The crystal field strength and the Racah parameters together with the nephelauxetic ratio are also determined for Mn4+ in the MGS lattice. High color rendition warm white-light-emitting diodes (WLEDs) based on the optimal phosphor MGS:1.5%Mn4+,1.5%Li+ possess a color rendering index and color temperature of 85.6 and 3658 K, respectively. Its feasibility for application in solid-state white lighting has been verified.