PD-1/PD-L1 pathway: Current research in breast cancer.

INTRODUCTION: Immunotherapy has shown encouraging outcomes in breast cancer (BC) treatment in recent years. The programmed cell death ligand 1 (PD-L1) transmembrane protein is suggested to function as a co-inhibitory factor in the immune response, where it collaborates with programmed cell death protein 1 (PD-1) to stimulate apoptosis, suppress cytokine release from PD-1 positive cells, and limit the growth of PD-1 positive cells. Furthermore, in many malignancies, PD-L1 reduces the immune system's response to neoplastic cells. These observations suggest that the PD-1/PD-L1 axis plays a vital role in cancer therapy and the regulation of cancer immune escape mechanisms. This review aimed to provide an overview of the functions of PD-1 and PD-L1 in BC cancer therapy. METHODS: This research design is a literature review. The style is a traditional review on topics or variables relating to the PD-1/PD-L1 pathway. A literature search was carried out using three online databases. RESULTS: The search using the keywords yielded a total of 248 studies. Each result was filtered again according to the inclusion and exclusion criteria, resulting in a final total of 4 studies to be included in the literature review. CONCLUSIONS: The combination of PD-1/PD-L1 is essential for many malignancies. According to the evidence presented, this combination presents both an opportunity and a challenge in cancer treatment. Since many solid cancers, especially BC, express high levels of PD-1/PD-L1, cancer treatment mainly involves targeted therapies.

Secretome of Hypoxia-Preconditioned Mesenchymal Stem Cells Enhance Angiogenesis in Diabetic Rats with Peripheral Artery Disease.

Background: Lower limb peripheral artery disease (PAD) is the main risk of diabetes mellitus which result to high mortality rate. Approximately, 50% of patients who receive several treatments have passed away or lost limbs at a year's follow-up. Secretome of hypoxia mesenchymal stem cells (S-MSCs) contains several active soluble molecules from hypoxia MSCs (H-MSCs) that capable inducing anti-inflammatory and vascular regeneration in PAD. Objective: In this study, we investigated the therapeutic potential of S-MSCs in improving dynamic function and angiogenesis of PAD diabetic rats. Methods: The PAD was established by the incision from the groin to the inner thigh and distal ligation of femoral arteries in rats with diabetes. Rats were administered with 200 µL and 400 µL S-MSCs that successfully filtrated using tangential flow filtration (TFF) system based on various molecular weight cut-off categories intravenously. ELISA assay was used to analyze the cytokines and growth factors contained in S-MSCs. Tarlov score were examined at day 1, 3, 5, 7, 10 and 14. The rats were sacrificed at day 14 and muscle tissues were collected for immunohistochemistry (IHC) and gene expression analysis. Results: ELISA assay showed that S-MSCs provides abundant level of VEGF, PDGF, bFGF, IL-10 and TGFß. In vivo administration of S-MSCs remarkably enhanced the Tarlov score. S-MSCs improved angiogenesis through enhancing VEGF gene expression and significantly increasing CD31 positive area in muscle tissue of PAD diabetic rats. Conclusion: Our findings suggest that S-MSCs could improves dynamic function and angiogenesis in PAD diabetic rats.

Random Blood Glucose, but Not HbA1c, Was Associated with Mortality in COVID-19 Patients with Type 2 Diabetes Mellitus-A Retrospective Study.

Previous studies have yielded inconsistent results on whether glycated hemoglobin (HbA1c) and random blood glucose (RBG) are associated with mortality of coronavirus disease 2019 (COVID-19) patients with type 2 diabetes mellitus (T2DM). This study aimed to assess the association of HbA1c and RBG with mortality among COVID-19 patients with T2DM. A retrospective study was conducted on 237 patients with COVID-19 and T2DM (survival (n = 169) and non-survival groups (n = 68)). Data on socio-demography, comorbidities, clinical symptoms, laboratory examination, and mortality were collected. Patients in the non-survival group had an older age range as compared with those in the survival group (60 (52.3-65.0) vs. 56.0 (48.5-61.5) years, p = 0.009). There was no statistical gender difference between the two groups. After matching was done, chronic kidney disease, NLR, d-dimer, procalcitonin, and random blood glucose were higher in the non-survival group compared to the survival group (p < 0.05). HbA1c levels were similar in survivors and non-survivors (8.7% vs. 8.9%, p=0.549). The level of RBG was independently associated with mortality of COVID-19 patients with T2DM (p = 0.003, adjusted OR per 1-SD increment 2.55, 95% CI: 1.36-4.76). In conclusion, RBG was associated with the mortality of COVID-19 patients with T2DM, but HbA1c was not.

Factors associated with disease severity of COVID­19 in patients with type 2 diabetes mellitus.

Diabetes mellitus causes a decline in immunological function, an increase in proinflammatory cytokines, and a prothrombotic state, thus providing risk factors for the severity of coronavirus disease 2019 (COVID-19) in patients with type 2 diabetes mellitus (T2DM). The aim of the present study was to analyze the risk factors associated with the severity of COVID-19 in patients with T2DM. A cross-sectional observational study was performed on 201 patients with T2DM from May 1 to August 31, 2020 and admitted to the isolation ward of Dr Soetomo General Hospital (Surabaya, Indonesia). The patients were divided into severe (108 cases; 53.7%) and non-severe (93 cases; 46.3%) groups, which were considered the dependent variables. Univariate and multivariate analysis was performed. The independent variables were age, sex, diabetes onset, chronic complications, presence of hypertension, randomized blood glucose, HbA1c, albumin, and neutrophil-lymphocyte ratio (NLR). A P-value <0.05 was considered to be statistically significant. The median age of the 201 subjects was 56 years, with 70.1% <60 years old, 52.7% male, 76.1% with diabetes onset <10 years, and 108 patients (53.7%) in severe condition. The results of the bivariate analysis revealed that diabetes onset >10 years (OR 2.5; P=0.011) was associated with severity of COVID-19 in patients with T2DM, however hypoalbumin (OR 1.93; P=0.054) was not associated with disease severity. Furthermore, multivariate analysis revealed that male sex (OR 2.07; P=0.042), age (≥60 years) (OR 2.92; P=0.008), HbA1c (≥8%) (OR 3.55; P=0.001), hypertension (OR 4.07; P=0.001), and an NLR ≥7.36 (OR 6.39; P=0.001) were associated with severe COVID-19. Collectively, it was revealed that increased NLR, hypertension, poor glycemic control, older age, and male sex were risk factors associated with the severity of COVID-19 among diabetic patients.

Tuberculosis Predictive Index for Type 2 Diabetes Mellitus Patients Based on Biological, Social, Housing Environment, and Psychological Well-Being Factors.

Indonesia is currently undergoing an epidemiological transition, with the double burden of disease due to increasing industrialization and urbanization leading to an increase in the prevalence of non-communicable diseases such as obesity and diabetes. On the other hand, the prevalence of infectious diseases such as tuberculosis remains high. Several factors were considered as risk factors in tuberculosis coincidence with type 2 diabetes mellitus. The purpose of this study was to develop a predictive index for tuberculosis in type 2 diabetes mellitus patients based on their biological, social, and environmental factors, and their psychological well-being as well. This case-control study involved 492 respondents consisting of 246 type 2 diabetes mellitus patients The variables studied were biological and social factors, the quality of their housing, and psychological well-being. Data analysis was conducted using a logistic regression test. The results showed that the predictive index formula was as follows: -3.218 + 0.867 × age + 1.339 × sex + 1.493 × history of contact with previous patient + 1.089 × glycemic control + 1.622 × tuberculosis clinical symptoms + 1.183 × body mass index + 0.891 × duration of diabetes mellitus + 0.454 × area of ventilation + 0.583 × psychological well-being. It is suggested that health workers, especially in primary health care facilities, will be able to increase the awareness of the risk of the coincidence of diabetes mellitus with tuberculosis.

Indonesia DIA-RAMADAN Study: A Real-life, Prospective and Observational of Gliclazide MR in Type-2 Diabetes Patients During Ramadan Fasting.

BACKGROUND: Sulfonylureas (SUs) have been widely used in many countries for T2DM treatment. Gliclazide is one of the SUs with the lowest risk of hypoglycemia; however, the safety and effectiveness of gliclazide MR during Ramadan has not yet been reported in Indonesia. This study aimed to assess safety, efficacy, and tolerability of gliclazide modified release (MR) during Ramadan fasting. METHODS: The study was a part of DIA-RAMADAN study, a prospective observational study with subjects of T2DM patients aged >18 years, who had either controlled or sub-optimally controlled blood glucose level, performed Ramadan fasting. Subjects had been treated with gliclazide MR for at least 90 days prior the study, and were examined for their body mass index (BMI), fasting plasma glucose (FPG) and HbA1c levels 6 to 8 weeks before Ramadan (V0) and 4 to 6 weeks after the end of Ramadan (V1). RESULTS: Out of 198 subjects participating in the study, there were only two subjects (1.0%) who reported symptomatic HEs (either confirmed or not confirmed) and no severe HEs had been reported. There were no significant changes in HbA1c and FPG levels (p>0.05). Interestingly, there was a reduction of bodyweight (-0.4kg) from pre- to post-Ramadan (p < 0.001). Almost no subjects reported discontinuation of gliclazide MR throughout the entire study; however, there was one subject who reported a change of diabetic treatment into diet only. CONCLUSION: gliclazide MR is safe, well tolerated and can maintain glycemic control effectively for Indonesian patients with T2DM who perform Ramadan fasting.

The expression of programmed death-ligand 1 and its association with histopathological grade, stage of disease, and occurrence of metastasis in breast cancer.

INTRODUCTION: Programmed death ligand 1 (PD-L1) plays a role in tumor escape and progression by inactivating T lymphocytes. The aim of the study reported here was to determine the relationship between the expression of PD-L1 and histopathological grade, stage of disease, and the occurrence of metastasis in breast cancer. METHODS: The observational cross-sectional study involved analyzing the expression of PD-L1 by immunohistochemistry. RESULTS: PD-LI was expressed in 43 of 60 patients with breast cancer (71.6%), mostly with a moderate histopathological grade (58.3%) and at an advanced stage (50%). Associations between the expression of PD-L1 and histopathological grade (p = 0.011), stage of disease (p = 0.009), and the occurrence of metastasis (p = 0.01) were significant, with an odds ratio of 5. CONCLUSION: The associations between the expression of PD-L1 and histopathological grade, disease stage, and occurrence of metastasis were all significant in cases of breast cancer in the sample. Those findings suggest that the expression of PD-L1 increases the progression of breast cancer.

A real-world study in patients with type 2 diabetes mellitus treated with gliclazide modified-release during fasting: DIA-RAMADAN.

AIMS: To explore the real-world safety and effectiveness of gliclazide modified release (MR) in patients with type 2 diabetes mellitus (T2DM) fasting during Ramadan. METHODS: DIA-RAMADAN (NCT04132934) was a prospective, international, observational study conducted in nine countries. Patients >18 years of age with T2DM (N = 1244) were examined at an inclusion visit (V0) occurring 6-8 weeks before the start of Ramadan. Patients received a diary to report treatment changes, hypoglycaemic events (HEs), and other adverse events. Gliclazide MR was taken once daily for 14-18 weeks. A second visit (V1) was conducted 4-6 weeks after the end of Ramadan. The primary endpoint was the proportion of patients reporting ≥1 symptomatic HE. Changes in HbA1c, fasting plasma glucose (FPG), and body weight were secondary endpoints. RESULTS: The proportion of patients reporting ≥1 symptomatic HE during Ramadan was low (2.2%) with no reported severe HEs. There was a significant reduction in HbA1c (-0.3%), FPG (-9.7 mg/dL), body weight (-0.5 kg) and body mass index (-0.2 kg/m2) between V0 and V1 (p < 0.001). CONCLUSIONS: Patients with T2DM treated with gliclazide MR during Ramadan have a low risk of hypoglycaemia and maintain glycaemic control and weight while fasting.

Metformin induced autophagy in diabetes mellitus - Tuberculosis co-infection patients: A case study.

Metformin (MET) is a potential combination drug to elevate anti-TB efficacy. However, the clinical effect, especially smear reversion, during metformin applied with anti-tuberculosis and insulin in patients with type 2 DM newly TB co-infection were remain unknown. An observational clinical study was done in DM newly TB co-infection outpatients at Surabaya Paru Hospital. This study evaluated MET therapy, at least 2 months, accompanying with insulin and anti-TB regimens and compared to comparison group. The smear, microtubule-associated Protein1 Light Chain 3B (MAP1LC3B) level, as the presentation of autophagy, Superoxide Dismutase (SOD) level, Interferon (IFN)-γ and Interleukin (IL)-10 levels were evaluated twice. From 42 participants in this study, 22 participants of observation group that received additional MET therapy, 100% had sputum smear reversion after 2-months intensive phase of anti-TB therapy. Whereas 25% of 20 participants of comparison group did not undergo reversion inserts sputum smear. As conclusion, MET has the potential of being an additive combination therapy to enhance the bactericidal effect of anti-TB on DM-TB coinfection patients. Metformin enhances the effects of anti-TB and insulin therapy in increasing the smear reversion by increasing autophagy.

A case risk study of lactic acidosis risk by metformin use in type 2 diabetes mellitus tuberculosis coinfection patients.

Metformin (MET) has possibilities to be utilized as an adjunct of tuberculosis (TB) therapy for controlling the growth of Mycobacterium tuberculosis (M. tuberculosis). MET enhances the production of mitochondrial reactive oxygen species and facilitates phagosome-lysosome fusion; those mechanism are important in M. tuberculosis elimination. Moreover, MET-associated lactic acidosis (MALA) needs to be considered and the incidence of MALA in patients with type 2 DM-TB coinfection remains unknown. This result contributes much to our understanding about the clinical effect of MET use in type 2 DM-TB coinfection. For the purpose of understanding the MET effect as an adjuvant therapy in TB therapy and insulin simultaneous therapy, an observational clinical study was done in type 2 DM newly TB coinfection outpatients at Surabaya Paru Hospital. Patients were divided into two groups. First group was MET group, in which the patients were given MET accompanying insulin and TB treatment regimens, the golden standard therapy of DM-TB coinfection. MET therapy was given for at least 2 months. Second group was non-MET group, in which the patients were given insulin and TB treatment regimens. The lactate levels in both groups were measured after 2 months. Among 42 participants, there was no case of lactic acidosis during this study period. Data were normally distributed; thus, we continued analysis of the difference using paired T-test with 95% confidence. There was no difference in lactate levels (p=0.396) after MET therapy compared to non-MET group. In this study involving patients with TB pulmonary diseases, there is neither evidence that MET therapy induced lactic acidosis event nor that it increased lactate blood level. Thus, we concluded that MET use in type 2 DM-TB coinfection did not induce lactic acidosis.

Safety and efficacy in early insulin initiation as comprehensive therapy for patients with type 2 diabetes in primary health care centers.

AIM: to analyze the safety and efficacy of early insulin initiation therapy for patients with type 2 diabetes mellitus (T2DM) in primary health care provided by general practitioners (GPs) in Surabaya, East Java, Indonesia. METHODS: pre-post study of ninety nine diabetic patients without previous insulin treatment with HbA1c levels >8% were involved in this study. The study was conducted in 10 primary health care centers in Surabaya between October 2011 to June 2012. Each patient received insulin therapy for 12 weeks. Laboratory examination was performed for each patient including fasting plasma glucose (FPG), 2 hours post-prandial plasma glucose (2hPPG) and HbA1c examination before and after the study. Self monitoring blood glucose (SMBG) examination was conducted in order to adjust the insulin dose and prevent the incidence of hypoglycemia. Data was statistically analyzed using paired-T test. RESULTS: FPG level was decreased from baseline data (209 mg/dL) to 152.07 mg/dL at the end of the study (56.93 mg/dl; p=0.0001). The average of 2hPPG level was also decreased from 313.00 mg/dl to 220.72 mg/dL ( 92.28 mg/dL; p=0.0001). HbA1c was reduced from 11.60% at baseline to 8.95% at the end of study ( 2.65%; p=0.0001). Hypoglycemia was found in 6 patients (6.06%) in this study, but all events were mild and did not need to be admitted to hospital. CONCLUSION: the safety of insulin therapy iniatiation might be provided by GPs at primary health centers with significant efficacy and minimal side effects.