Comparison between sodium-glucose cotransporter 2 inhibitors and dipeptidyl peptidase 4 inhibitors on the risk of incident cancer in patients with diabetes mellitus: A real-world evidence study.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have been demonstrated to be associated with cancer cell mechanisms. However, whether they increase the risk of cancer remains unclear. Thus, this study aimed to determine the association between SGLT-2i use and the incidence of cancer in patients with diabetes mellitus (DM) in Taiwan. MATERIALS AND METHODS: This retrospective cohort study was based on the Taiwan National Health Insurance database. The study population comprised patients with DM, and those who first used SGLT-2is during 2016-2018 were assigned to the study group. Greedy propensity score matching was performed to select patients who first used dipeptidyl peptidase 4 inhibitors (DPP-4is), and these patients were assigned to the control group. A Cox proportional hazards model was used to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cancer risk in the study and control groups; this model was adjusted for demographic characteristics, DM severity, comorbidities and concomitant medication use. RESULTS: After controlling for relevant variables, the SGLT-2i cohort (aHR = 0.90, 95% CI = 0.87-0.93) had a significantly lower risk of developing cancer than the DPP-4i cohort, particularly when the SGLT-2i was dapagliflozin (aHR = 0.91, 95% CI = 0.87-0.95) or empagliflozin (aHR = 0.90, 95% CI = 0.86-0.94). Regarding cancer type, the SGLT-2i cohort's risk of cancer was significantly lower than that of the DPP-4i cohort for leukaemia, oesophageal, colorectal, liver, pancreatic, lung, skin and bladder cancer. CONCLUSIONS: SGLT-2i use was associated with a significantly lower risk of cancer than DPP-4i use.

The effect of joint involvement of nurse and physician in hospice care on terminal cancer patients on do-not-resuscitate orders signed by surrogates.

OBJECTIVES: Patients with terminal cancer often experience physical and mental distress. Signing a do-not-resuscitate order (DNR) is crucial to protect against invalid treatment. This study aims to explore the effect of hospice shared care intervention by medical staff on the completion of a DNR-S (DNR order signed by surrogates) for patients with terminal cancer. METHOD: The cross-sectional study in this research involved secondary analysis of data from the 2011-2015 clinical cancer case management database of a medical center in central Taiwan. Those with a DNR order signed by patients (DNR-P) or DNR-S before the hospice shared care consultation were excluded from this study; a total of 1,306 patients with terminal cancer were selected. RESULTS: This study demonstrated that the percentage of DNR-S after consultation involving both nurse and physician was 75.4%. With other variables controlled, the number of DNR-Ss after consultation with a nurse was significantly lower [odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.42-0.75] and that of DNR-Ss after consultation involving both nurse and physician was significantly higher (OR = 1.35, 95% CI = 1.01-1.79), than that of DNR-Ss after consultation with only the physician. SIGNIFICANCE OF RESULTS: Joint involvement of the nurse and physician in hospice care provides sufficient information to patients and family with terminal cancer about their condition and enhances doctor-patient communication. This effectively assists patients with terminal cancer and their family members in making the major decision of signing a DNR, alleviates the concerns of patients and family members about signing a DNR, and reduces terminal cancer patients' pain at the end of life to ensure that they die in peace and dignity.

The Protective Effects of Influenza Vaccination in Elderly Patients with Breast Cancer in Taiwan: A Real-World Evidence-Based Study.

In elderly patients with newly diagnosed breast cancer, clarity is lacking regarding the effects of influenza vaccines, particularly on clinical outcomes. This study conducted two nationwide, population-based, and propensity score-matched cohorts to estimate and compare the protective effects of influenza vaccine in elderly women and elderly patients with breast cancer. Data were derived from the National Health Insurance Research Database and Cancer Registry Database. Generalized estimating equations (GEEs) were used to compare outcomes between the vaccinated and unvaccinated cohorts. Adjusted odds ratios (aORs) were used to estimate the relative risks, and stratified analyses in the breast cancer cohort were performed to further evaluate elderly breast cancer patients undergoing a variety of adjuvant therapies. The GEE analysis showed that the aORs of death and hospitalization, including for influenza and pneumonia, respiratory diseases, respiratory failure, and heart disease, did not significantly decrease in vaccinated elderly patients with newly diagnosed breast cancer. Conversely, the aORs of all influenza-related clinical outcomes were significantly decreased in elderly women. No protective effects of influenza vaccination were found in the elderly patients with a newly diagnosed breast cancer. More studies focusing on identifying strategies to improve the real-world effectiveness of influenza vaccination to the immunocompromised are needed. Our clinical outcomes will be valuable for future public health policy establishment and shared decision making for influenza vaccine use in elderly patients with newly diagnosed breast cancer. According to our findings, regular influenza vaccine administration for elderly patients with newly diagnosed breast cancer may be reconsidered, with potential contraindications for vaccination. On the other hand, implementing the vaccination of close contacts of patients with breast cancer may be a more important strategy for enhancing protection of those fragile patients.

Risk of Non-Hodgkin Lymphoma among Patients with Hepatitis B Virus and Hepatitis C Virus in Taiwan: A Nationwide Cohort Study.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with an increased risk of developing non-Hodgkin lymphoma (NHL); however, adequate data corroborating these associations are lacking. Therefore, a study based on the national database was performed to investigate the correlation between HBV and HCV with NHL in Taiwan. This research was a retrospective cohort study using a nationally representative database established by the Health and Welfare Data Science Center of the Ministry of Health and Welfare, Taiwan. The participants were patients with HBV and HCV, analyzed using the propensity score matching method. The study results indicated that the incidence rate of NHL (0.13%) was significantly higher than that in patients from the general population. After controlling related variables, the hazard ratio (HR) of the incidence of NHL in patients with hepatitis was 2.37 (95% CI, 1.93-2.91). Furthermore, the incidence of NHL in patients with HBV was significantly higher than in patients from the general population (HR, 2.49; 95% CI, 1.94-3.19). The incidence of NHL in patients with HCV was significantly higher than in patients from the general population (HR, 2.36; 95% CI, 1.73-3.22). This study indicated that HBV and HCV significantly increase the risk of NHL.

Protective effects of Antrodia camphorata extract against hypoxic cell injury and ischemic stroke brain damage.

Ischemic stroke is the most prevalent stroke condition in the world resulted in either a transient ischemic attack or long-lasting neurological problems due to the interrupted or reduced blood flow to the brain. Antrodia camphorata is a well-known medicinal mushroom native to Taiwan and is familiar due to its medicinal effects. The current study investigated the protective effect of A. camphorata-alcohol extracts (AC-AE) against cobalt (II) chloride (CoCl2 )-induced oxidative stress in vitro and ischemia/reperfusion-induced brain injury in vivo. The rats were pre-treated with AC-AE for 4 weeks. Our results showed that AC-AE reduced cell damage and decreased reactive oxygen species (ROS) production in C6 and PC12 cells under CoCl2 -induced hypoxic condition. AC-AE doses (385, 770, 1,540 mg/kg/day, 4 weeks) increased nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA expressions and decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expressions in Sprague Dawley rat. Besides, it decreased stroke infarct size and increased the level of antioxidants in both brain and serum. Furthermore, it reduced the formation of malondialdehyde (MDA) after ischemia/reperfusion (I/R). Our results suggested that AC-AE exerted an effective reduction of ischemia stroke by regulating ROS production.

Neurotrophic and neuroprotective potential of human limbus-derived mesenchymal stromal cells.

BACKGROUND AIMS: The purpose of this study was to examine neurotrophic and neuroprotective effects of limbus stroma-derived mesenchymal stromal cells (L-MSCs) on cortical neurons in vitro and in vivo. METHODS: Cultured L-MSCs were characterized by flow cytometry and immunofluorescence through the use of specific MSC marker antibodies. Conditioned media were collected from normoxia- and hypoxia-treated L-MSCs to assess neurotrophic effects. Neuroprotective potentials were evaluated through the use of in vitro hypoxic cortical neuron culture and in vivo rat focal cerebral ischemia models. Neuronal morphology was confirmed by immunofluorescence with the use of anti-MAP2 antibody. Post-ischemic infarct volume and motor behavior were assayed by means of triphenyltetrazolium chloride staining and open-field testing, respectively. Human growth antibody arrays and enzyme-linked immunoassays were used to analyze trophic/growth factors contained in conditioned media. RESULTS: Isolated human L-MSCs highly expressed CD29, CD90 and CD105 but not CD34 and CD45. Mesenchymal lineage cell surface expression pattern and differentiation capacity were identical to MSCs derived form human bone marrow and adipose tissue. The L-MSC normoxic and hypoxic conditioned media both promoted neurite outgrowth in cultured cortical neurons. Hypoxic conditioned medium showed superior neurotrophic function and neuroprotective potential with reduced ischemic brain injury and improved functional recovery in rat focal cerebral ischemia models. Human growth factor arrays and enzyme-linked immunoassays measurements showed neuroprotective and growth-associated cytokines (vascular endothelial growth factor [VEGF], VEGFR3, brain-derived neurotrophic factor, insulin-like growth factor -2 and hepatocyte growth factor) contained in conditioned media. Hypoxic exposure caused VEGF and brain-derived neurotrophic factor upregulation, possibly contributing to neurotrophic and neuroprotective effects. CONCLUSIONS: L-MSCs can secrete various neurotrophic factors stimulating neurite outgrowth and protecting neurons against brain ischemic injury through paracrine mechanism.

Notch prevents transforming growth factor-beta-assisted epithelial-mesenchymal transition in cultured limbal progenitor cells through the induction of Smad7.

PURPOSE: Continuous culture of limbal epithelial stem cells (LSCs) slows down proliferation, which inevitably results in differentiation. Transforming growth factor-beta (TGFß)-assisted epithelial-mesenchymal transition (EMT) is often found in the late stage of LSC culture. Thus, EMT is proposed to be part of the mechanism responsible for the loss of LSCs in culture. To explore the regulation mechanism of EMT, we investigated the early stage culture for factor(s) that may potentially prevent EMT. METHODS: LSCs from the corneal limbus region of rabbits were isolated and expanded to confluence in culture (P0), and then serial passage of these LSCs (P1 to P3) was performed. EMT in LSCs was induced with TGFß1, and the corresponding EMT signaling was confirmed with Smad2/3 phosphorylation. The expression of mesenchymal markers, including alpha-smooth muscle actin (α-SMA) and vimentin, was determined with western blot analysis. Proteins extracted from different passaged cells were also subjected to western blot analysis of TGFß signaling components, including TGFß1, TGFß receptor I/II, and Smad2/3 as well as Smad7, the main negative regulator of TGFß signaling. The mitogenic response was measured with the bromodeoxyuridine (BrdU) labeling index and real-time PCR using primers for Ki67. N-(N-[3,5-difluorophenacetyl]-l-alanyl)-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor, and Jagged-1 Notch ligand were used to block and activate Notch signaling, respectively, and their efficacy was evaluated by determining the expression of Hes1, a Notch signaling target. RESULTS: Mesenchymal marker induction and growth arrest were found in the TGFß1-treated P1 cells, and the changes were less significant in the TGFß1-treated P0 cells. Western blot analysis confirmed that the expressed levels of TGFß signaling components, including TGFß1, TGFß receptor I/II, and Smad2/3, were relatively stable with passages. In contrast, the expression of Hes1 and Smad7 markedly decreased after the first passage, and with each passage, the levels diminished even further. Hes1 and Smad7 were expressed only in the limbal epithelium and not in the corneal epithelium. DAPT effectively blocked the expression of Hes1. DAPT also dose-dependently suppressed Smad7 expression in P0 cells, which was associated with the susceptibility of P0 cells to TGFß1-induced Smad2/3 phosphorylation, EMT formation, and growth arrest. Reciprocally, Jagged-1 upregulated Smad7 expression in LSCs against TGFß signaling. CONCLUSIONS: These findings indicate that Smad7 plays a crucial role in antagonizing EMT induced by TGFß signaling and support our proposition that Smad7 is a Notch signaling target in LSCs, and may mediate the Notch function in preventing the occurrence of EMT.

Lowered cancer risk with ACE inhibitors/ARBs: a population-based cohort study.

There are conflicting reports on cancer risk associated with angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs). This retrospective cohort study was conducted to analyze the risk of cancer development in patients who received ACE inhibitors/ARBs as treatment for essential hypertension. Using the Taiwan National Health Insurance Research Database, 297,688 eligible study patients with essential hypertension were identified. According to their antihypertensive prescriptions, the study patients were stratified into an ACE inhibitor group, an ARB group, or a control group. After matching, participants were observed for the occurrence of cancer. In the ACE inhibitor group compared with the control group, the hazard ratio was 0.51 (95% confidence interval, 0.39-0.68). In the ARB group compared with the control group, the hazard ratio was 0.8 (95% confidence interval, 0.65-0.97). Regular use of ACE inhibitors/ARBs was not associated with an increased risk of cancer development and was actually found to decrease overall cancer risk in this study.

Gene therapy of focal cerebral ischemia using defective recombinant adeno-associated virus vectors.

This review presents our experience and results concerning cerebral stroke gene therapy with a rat model subjected to rAAV-vector delivered IL-1ra and GDNF. The methodology involving the production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus and the creation of a tri-vessel ligation model of focal ischemic cerebral stroke in rats are described in detail. Furthermore, a literature review of other viral vectors, murine models of focal cerebral ischemia and candidates for therapeutic transgenes used for cerebral stroke gene therapy are presented. Lastly, the potentials and limitations of stroke gene therapy are discussed adding an analysis of possibilities of future experiment designs.

Gene treatment of cerebral stroke by rAAV vector delivering IL-1ra in a rat model.

In this study, we injected recombinant adeno-associated virus (rAAV) vectors expressing the interleukin-1 receptor antagonist (rAAV-IL-1ra) into the cortex of rats experiencing transient cerebral ischemia. An accumulation of IL-1ra in cortical tissues of rAAV-IL-1ra-injected animals was confirmed by ELISA. Triphenyltetrazolium chloride (TTC) staining of viable brain tissue revealed that the rAAV-delivered IL-1ra gene could rescue the brain tissues from ischemia-induced injury. Cortical tissues that received rAAV-IL-1ra injections had both significantly smaller total volumes of infarction as well as smaller areas of infarction on each brain slice when compared with the control models. In situ labeling analysis demonstrated significant reduction of apoptotic cells in cortical tissues rescued by rAAV-IL-1ra. Immunohistochemistry staining revealed that the rescued brain tissues contained the same levels of neuronal cells as contralateral undamaged brain tissues. These findings confirmed that the rAAV delivering the IL-1ra gene is a potential therapy for stroke.

Gene therapy for treatment of cerebral ischemia using defective recombinant adeno-associated virus vectors.

In this review we present our results and experiences in performing gene therapy of cerebral stroke using recombinant adeno-associated virus (rAAV) vectors in a rat model. The methodologies involving the production of AAV vectors, gene transfer to the brain, and a trivessel ligation model of focal ischemic cerebral stroke in rats are described. Furthermore, a brief description of other viral vectors and candidates of therapeutic transgenes used for gene therapy of cerebral stroke are presented. The potential advantages and limitations of stroke gene therapy are also discussed with the intention of outlining the design of more appropriate experiments.