The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators that Inhibit their Activity.

The crucial role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.g., the epidermal growth factor receptor (EGFR). Considering their regulatory roles in cancer, therapeutics targeting various extracellular proteases have been discovered. These include the metal-binding agents di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which increase c-MET degradation by multiple mechanisms. Both the direct and indirect inhibition of protease expression and activity can be achieved through metal ion depletion. Considering direct mechanisms, chelators can bind zinc(II) that plays a catalytic role in enzyme activity. In terms of indirect mechanisms, Dp44mT and DpC potently suppress the expression of the kallikrein-related peptidase-a prostate-specific antigen-in prostate cancer cells. The mechanism of this activity involves promotion of the degradation of the androgen receptor. Additional suppressive mechanisms of Dp44mT and DpC on matrix metalloproteases (MMPs) relate to their ability to up-regulate the metastasis suppressors N-myc downstream regulated gene-1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion.

Drug Repositioning of the α1-Adrenergic Receptor Antagonist Naftopidil: A Potential New Anti-Cancer Drug?

Failure of conventional treatments is often observed in cancer management and this requires the development of alternative therapeutic strategies. However, new drug development is known to be a high-failure process because of the possibility of a lower efficacy than expected for the drug or appearance of non-manageable side effects. Another way to find alternative therapeutic drugs consists in identifying new applications for drugs already approved for a particular disease: a concept named "drug repurposing". In this context, several studies demonstrated the potential anti-tumour activity exerted by α1-adrenergic receptor antagonists and notably renewed interest for naftopidil as an anti-cancer drug. Naftopidil is used for benign prostatic hyperplasia management in Japan and a retrospective study brought out a reduced incidence of prostate cancer in patients that had been prescribed this drug. Further studies showed that naftopidil exerted anti-proliferative and cytotoxic effects on prostate cancer as well as several other cancer types in vitro, as well as ex vivo and in vivo. Moreover, naftopidil was demonstrated to modulate the expression of Bcl-2 family pro-apoptotic members which could be used to sensitise cancer cells to targeting therapies and to overcome resistance of cancer cells to apoptosis. For most of these anti-cancer effects, the molecular pathway is either not fully deciphered or shown to involve α1-adrenergic receptor-independent pathway, suggesting off target transduction signals. In order to improve its efficacy, naftopidil analogues were designed and shown to be effective in several studies. Thereby, naftopidil appears to display anti-cancer properties on different cancer types and could be considered as a candidate for drug repurposing although its anti-cancerous activities need to be studied more deeply in prospective randomized clinical trials.

Informal carers' experiences and needs when supporting patients through chemotherapy: a mixed method study.

Informal carers provide important emotional support to patients having chemotherapy and assistance in monitoring and managing side-effects. If they are inadequately supported in this, patient and carer morbidity may result. This study explored needs of informal carers supporting patients with cancer having chemotherapy. The study used a mixed methods approach. Carers of colorectal or lymphoma cancer patients at one comprehensive cancer centre participated. Questionnaire data informed semi-structured interviews conducted with a subsample of respondents. Interviews were analysed using Framework analysis. Questionnaire data were analysed descriptively. Fifty-nine informal carers were invited to participate; 48 returned the questionnaire (response rate 81%) and 13 were interviewed. Informal carers' needs for information about chemotherapy and its side-effects were largely met although a third felt completely or somewhat unprepared to deal with particular symptoms experienced by patients at home. Many carers had unmet needs regarding financial support and their own needs as carers. Assertiveness was important to many caring roles, but it appeared difficult for informal carers to adopt when they were unsupported in this and their role was unrecognised by health professionals. Future research should develop interventions to systematically prepare carers for their carer role, improve carer involvement and ultimately improve patient outcomes.

Truth-telling in Oncology: Egyptian Patients' Attitudes and Preferences.

OBJECTIVE: Truth-telling in oncology is a major challenge, particularly in the absence of disclosure protocols in Egypt and the lack of Egyptian studies examining patients' preferences regarding cancer disclosure. This study aimed to reveal the preferences of patients seeking care at the National Cancer Institute - Cairo University regarding disclosing cancer diagnosis and the type and amount of information to be told. METHODS: This cross-sectional study was conducted on 200 patients selected consecutively from those attending the outpatient clinics of the National Cancer Institute - Cairo University. Face-to-face interviews were performed with the patients according to a structured questionnaire. The questionnaire consisted of five parts: socio-demographic characteristics, knowledge about cancer disease, attitudes towards cancer disease, experience during the disclosure of the diagnosis, and preferences regarding disclosure of cancer diagnosis. RESULTS: Most patients (89.5%) preferred to know the diagnosis. Of them, 94.4% wished to know from the physician. No agreement was found between most patients' preferences and physicians' practice. On multivariate logistic regression analysis, patients' education was the only significant predictor of the preference to know the diagnosis (OR = 5.298, 95% CI = 1.258 - 22.301, P = 0.023). CONCLUSION: Patients have a great desire to know the diagnosis and other information related to treatment and prognosis.

Transitional Cancer Care Program from Hospital to Home in the Health Care System of Iran.

OBJECTIVES: Transitional care program refers to the health care continuity during transferring from one health care setting to another or to home. This is an essential program for cancer patients and reduces the risk of unnecessary hospital admissions as well as the complications of the disease. The aim of this study was to develop a transitional cancer care program from hospital to home in the health care system of Iran. METHODS: This study is a health policy and system research. It was conducted in four stages from October 2019 to January 2020. The first stage was a qualitative study. The qualitative data were collected through semi-structured interviews with 24 participants and a focus group with eight experts. In the second stage, a literature review of transitional care models was carried out. The initial version of the transitional cancer care program was developed based on the qualitative results and the literature review in the third stage. The validity and feasibility of the program were assessed using the Delphi study in the fourth stage. RESULTS: Six major categories were extracted from the qualitative results, consisting of "integrated services for the continuity of care", "holistic care", "care standardization", "the use of telemedicine", "the transparency of rules" and "the care process provision". Using these results and extracted the three common models of transitional care, the initial program was developed in three phases of pre-discharge, post-discharge, and transitional care with six protocols. The content validity of the program (98.7%) and its feasibility (95.8%) were approved by experts in the Delphi rounds. CONCLUSIONS: It is necessary to revise hospitals' discharge program, and home health care center's plan for admission and delivering health care services for cancer patients. Also, a pilot program is necessary to find the system advantages and disadvantages.
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The Effective Control of Hyperuricemia in Cancer Patients: A New Recombinant Conjugated Variant of Urate Oxidase.

OBJECTIVE: Management of hyperuricemia is crucial to controlling tumor lysis syndrome (TLS) during cancer therapy. Urate oxidase (UOX) that catalyzes the enzymatic oxidation of uric acid into allantoin, is effective in lowering plasma uric acid levels and controlling hyperuricemia. Recently, we developed a new recombinant conjugate variant of UOX therapeutic drug using PASylation technology. This study was designed to evaluate the stability, plasma half-life and immunogencity of PASylated UOX. METHODS: A recombinant variant of PASylated UOX from the Aspergillus flavus was manufactured using bioinformatics and experimental techniques. Ex vivo evaluation of stability of PASylated UOX was done in 50% human serum. For half-life test, recombinant PASylated UOX and rasburicase were administered at 1.5 mg/kg to 10 rats in two different groups and samples were collected after injection Production of antibodies against PASylated drug was also assayed. RESULTS: Residual activity of PASylated UOX in 50% human serum was higher than rasburicase and native UOX. Stability of PASylated UOX at 25°C and 37°C was also higher than rasburicase and native UOX. The PASylated half-life was ~32.1 hours, whereas half-life for rasburicase and native UOX was ~25.1 and ~22.8 hours, respectively. In immunogenicity examination, there is 33% and 36% decrease in the absorbance of native UOX and rasburicase, respectively when compared with that of PASylated UOX. CONCLUSION: Our data confirmed the efficacy and stability of PASylated UOX in comparison to the rasburicase. In summary, the results indicated that PASylated UOX drug is effective at lowering plasma uric acid levels with prolonged plasma half-life and decreased cost.
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Assessing the Relationship between Socio-demographic, Clinical Profile and Financial Toxicity: Evidence from Cancer Survivors in Sarawak.

BACKGROUND: Patient's financial ability is always the most critical imputes to treatment choice and adherence; as it translates into health outcomes such as survival rate and quality of life. Cancer care is likely to affect the patient's financial well-being, putting huge financial pressure to the families. Therefore, it is imperative to understand the confounding factors of financial toxicity among cancer survivors along the course of survivorship. METHODS: This study was designed in the form of cross-sectional analysis, in which, cancer survivors were recruited from the Sarawak General Hospital, the largest tertiary and referral public hospital in Sarawak. To capture the financial toxicity of the cancer survivors, the Comprehensive Score for Financial Toxicity (COST) instrument in its validated form was adopted. Multivariable logistic regression analysis was applied to determine the relationship between financial toxicity (FT) and its predictors. RESULTS: The median age of the 461 cancer survivors was 56 while the median score of COST was 22.0. Besides, finding from multivariable logistic regression revealed that low income households (OR: 6.893, 95% CI, 3.109-15.281) were susceptible to higher risk of financial toxicity, while elderly survivors above 50 years old reported a lower risk in financial toxicity. Also, survivors with secondary schooling (OR:0.240; 95%CI, 0.110-0.519) and above [College or university (OR: 0.242; 95% CI, 0.090-0.646)] suffer a lower risk of FT. CONCLUSION: Financial toxicity was found to be associated with survivors age, household income and educational level. In the context of cancer treatment within public health facility, younger survivors, households from B40 group and individual with educational attainment below the first level schooling in the Malaysian system of education are prone to greater financial toxicity. Therefore, it is crucial for healthcare policymakers and clinicians to deliberate the plausible risk of financial toxicity borne by the patient amidst the treatment process.