Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive visceral malignancy originating from pancreatic duct cells. Despite advances in detection, diagnostic procedures and surgical and oncologic treatment, the overall prognosis remains dismal. GLOBOCAN 2020 ranks PDAC as the 7 th leading cause of all cancer deaths. There are no reliable statistics on the incidence of PDAC in South Africa. The National Cancer Registry South Africa of 2017 reports that PDAC accounts for 0.53% and 0.58% of all cancers in females and males respectively. However, this low incidence may be due to underreporting, as the diagnoses are based on positive histology which are performed on only a small proportion of PDAC patients reported by the National Health Laboratory Service (NHLS), only one of several laboratories in South Africa. The overall 5-year survival rate for all PDAC patients is reported to be less than 5%, and the overall median survival is 4-7 months from the time of diagnosis. Surgical resection offers the only chance of cure, but as few as 10% of patients are treated with curative intent with 5-year survival rates of 15-25%. A median survival of 2.8-5.7 months has been reported for patients with metastatic disease. Early symptoms of PDAC such as loss of appetite, weight loss and fatigue are vague and non-specific, which often leads to a delay in the diagnosis. Approximately 80% of patients who have PDAC involving the head of the pancreas present with painless jaundice. In those with advanced disease other digestive symptoms such as loss of weight, nausea and vomiting, bloating, altered bowel habits and backache are prominent. Because of the severity of symptoms, the small proportion of patients who are eligible for curative treatment, and the dismal overall survival, palliative treatment is an important component of the overall treatment of PDAC. In this respect information provided by health-related quality of life (HRQOL) assessments, which refer to the subjective experiences and perceptions of patients regarding their health, illness, and medical interventions, and how these affect their everyday life and functioning, are invaluable for planning and assessing the effect of palliative treatment. HRQOL assessment quantifies not only the actual symptoms but also the effect of the disease on a person in his or her totality. Many studies that report on HRQOL in PDAC are conducted in sponsored clinical trials and are guided by regulatory requirements. These studies typically include highly selected cohorts defined by strict inclusion and exclusion criteria, and results do not reflect HRQOL in the larger unselected patient population. Several nonclinical trial PDAC HRQOL studies have been done both in patients who underwent an operation and those who received palliative treatment. The prognostic value of HRQOL parameters have also been investigated. Very little data are available on the HRQOL of PDAC patients in low- and middle-income countries (LMICs), and to our knowledge no data have been published on the HRQOL of PDAC patients in South Africa. The aim of this research was to assess HRQOL in a South African PDAC patient cohort presenting at a major hepato-pancreato-biliary (HPB) academic referral centre, and to determine the possible clinical applications of HRQOL outcomes in the management of these patients, treated with either curative or palliative intent. The European Organisation for Research and Treatment of Cancer (EORTC)-QLQ-C30 and EORTC-QLQ-PAN26 instruments were used in a longitudinal design study to allow for comparisons with baseline (BL) reports at regular intervals, thereby identifying statistically significant and clinically meaningful changes that may have occurred over time. As in previous publications, a high mortality and decreasing compliance over time in both the curative intended and palliative cohorts were noted. In contrast to patients who underwent an operation in whom the functional and symptom scales and scores fluctuated notably between time points, the same remained relatively stable in the patients who received palliative treatment. Some interesting observations regarding the possible prognostic value of HRQOL outcomes in the respective treatment groups need to be further investigated in larger patient cohorts. Some of the lessons learnt in this study from a LMIC, may be of value in planning subsequent tumour-related HRQOL studies in LMICs, regardless of tumour type.

Background: The literature tends to support the notion that diabetic patients typically suffer from tibio-peroneal artery occlusive disease (1) (2) (11) (5) (10) (8) with relative sparing of the foot arteries (1). This study seeks to investigate the pattern and distribution of peripheral artery occlusive disease and the arterial foot arch status in diabetic patients with critical limb ischaemia Methods: This is a one year prospective study -(January 2014 to December 2014) carried out on consecutive patients seen at Groote Schuur Hospital, Vascular Department. The inclusion criteria is: diabetic patients ≥18 years of age with critical limb ischemia who had pre- and post-intervention vascular imaging. The calculated minimum sample size of 63 limbs [756 patency levels (63x12)] was needed to achieve a power of 86% to detect a difference of 0.1900 (19%) with a target significance level of 0.05 (using PASS 11 software). The equality of distribution of categories was analyzed using the One sample Chi-square test (SPSS 22) with our Null hypothesis (N0) assuming that categories occur with equal proportions. In this case categories refers to the 5 patency levels used in this study. All 12 main arteries from infra-renal aorta to crural arteries had their patency levels graded from category 1 to category 5 (widely patent to occluded). The findings were then stratified according to gender, age group ( <40 years, 40-54 years and ≥ 55 years) and risk factor combinations [ Group1 = (DM, HPT, Dyslipidemia); Group 2= (DM, HPT, dyslipidemia, exsmoker); Group 3 = (DM, HPT, dyslipidemia, smoker)]. The three risk combination groups formed the majority of our study group (79%).

Background: Colorectal cancer (CRC) is the 5th most common cancer in subSaharan Africa (SSA) and the 3rd most common cancer in Southern Africa. CRC characteristics in SSA, including anatomic distribution, are not well described. Objective: To describe patient characteristics and anatomic location of colorectal adenocarcinoma (CRC-AC) in South Africa. Design: This was a retrospective study of CRC using the South African National Cancer Registry from 2006-2011. Main Outcome Measures: Patient age, gender, racial/ethnic group, province, histology type, and tumour location. Results: 6146 patients were included in the analysis. Among patients with adenocarcinomas, the median age of presentation was 60 (interquartile range, 49-70) years. 1372 (25%) of patients were < 50 years and 2870 (52%) were male. There were 5498 (89%) cases of adenocarcinoma (AC). 1277 (26%) CRC-AC were right colonic lesions, 1214 (25%) were left colonic lesions, and 2404 (49%) lesions were located in the rectum. Patients ≥ 50 years at presentation (OR=1.29. p< 0.001) and from Limpopo province (OR=1.46, p=0.029) were more likely to have left colonic and rectal adenocarcinoma on multivariate analysis. Patients who were black (OR=1.67, p< 0.001), had right colonic lesions (OR=1.25, p=0.007), and were from Mpumalanga (OR=1.67, p=0.007), Limpopo (OR=1.60, p=0.002), or Northwest (OR=1.76, p=0.001), were significantly associated with early onset adenocarcinoma. Conclusion: CRC-AC in South Africa presents at an earlier age than in HICs, such as the US. Early-onset CRC is higher in black South Africans who live in Mpumalanga, Limpopo, and Northwest in comparison with other provinces. The majority of colorectal cancer were leftsided and rectal; thus screening flexible sigmoidoscopy should be considered. Further studies on the age-specific incidence and the genetics and epigenetics of CRC-AC in South Africa are needed.

Liver dysfunction is strongly associated with poor survival of sepsis patients. Cytosolic lipopolysaccharide (LPS) sensing by Caspase-4/5/11 for pyroptosis activation is a major driver of the development of sepsis. Studies in macrophages and endothelial cells have demonstrated that LPS is inactivated by acyloxyacyl hydrolase (AOAH) and leading to desensitizing Caspase-4/5/11 to LPS. However, little is known about the cytosolic LPS-induced pyroptosis in hepatocytes during sepsis. Heat shock protein 12A (HSPA12A) is a novel member of the HSP70 family. Here, we report that LPS increased HSPA12A nuclear translocation in hepatocytes, while knockout of HSPA12A (Hspa12a−/−) in mice promoted LPS-induced acute liver injury. We also noticed that the LPS-induced Caspase-11 activation and its cleavage of gasdermin D (GSDMD) to produce the membrane pore-forming GSDMDNterm (markers of pyroptosis) were greater in livers of Hspa12a−/− mice compared with its wild type controls. Loss- and gain-of-function studies showed that HSPA12A deficiency promoted, whereas HSPA12A overexpression inhibited, cytosolic LPS accumulation, Caspase-11 activation and GSDMDNterm generation in primary hepatocytes following LPS incubation. Notably, LPS-induced AOAH expression was suppressed by HSPA12A deficiency, whereas AOAH overexpression reversed the HSPA12A deficiency-induced promotion of LPS-evoked and Caspase-11-mediated pyroptosis of hepatocytes. In-depth molecular analysis showed that HSPA12A interacted directly with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and increased its nuclear translocation, thereby inducing AOAH expression for cytosolic LPS inactivation, which ultimately leading to inhibition of the Caspase-11 mediated pyroptosis of hepatocytes. Taken together, these findings revealed HSPA12A as a novel player against LPS-induced liver injury by inhibiting cytosolic LPS-induced hepatocyte pyroptosis via PGC-1α-mediated AOAH expression. Therefore, targeting hepatocyte HSPA12A represents a viable strategy for the management of liver injury in sepsis patients.

Obesity is one of the most serious public health problems. Peroxisome proliferator-activated receptor γ (PPARγ) plays the master role in adipocyte differentiation for obesity development. However, optimum anti-obesity drug has yet been developed, mandating more investigation to identify novel regulator in obesity pathogenesis. Heat shock protein 12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that obese patients showed increased adipose HSPA12A expression, which was positively correlated with increase of body mass index. Intriguingly, knockout of HSPA12A (Hspa12a−/−) in mice attenuated high-fat diet (HFD)-induced weight gain, adiposity, hyperlipidemia, and hyperglycemia compared to their wild type (WT) littermates. Increased insulin sensitivity was observed in Hspa12a−/− mice compared to WT mice. The HFD-induced upregulation of PPARγ and its target adipogenic genes in white adipose tissues (WAT) of Hspa12a−/− mice were also attenuated. Loss- and gain-of-function studies revealed that the differentiation of primary adipocyte precursors, as well as the expression of PPARγ and target adipogenic genes during the differentiation, was suppressed by HSPA12A deficiency whereas promoted by HSPA12A overexpression. Importantly, PPARγ inhibition by GW9662 reversed the HSPA12A-mediated adipocyte differentiation. On the other hand, HSPA12A expression was downregulated by PPARγ inhibition but upregulated by PPARγ activation in primary adipocytes. A direct binding of PPARγ to the PPAR response element in the Hspa12a promoter region was confirmed by chromatin immunoprecipitation assay, and this binding was increased after differentiation of primary adipocytes. These findings indicate that HSPA12A is a novel regulator of adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ. HSPA12A inhibition might represent a viable strategy for the management of obesity in humans.

This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Angiogenesis is essential for cardiac functional recovery after myocardial infarction (MI). HSPA12B is predominately expressed in endothelial cells and required for angiogenesis. Yes-associated protein (YAP) plays an important role in tumor angiogenesis. This study investigated the cooperative role of HSPA12B and YAP in angiogenesis after MI. Silencing of either HSPA12B or YAP impaired hypoxia-promoted endothelial cell proliferation and angiogenesis. Deficiency of HSPA12B suppressed YAP expression and nuclear translocation after hypoxia. Knockdown of YAP attenuated hypoxia-stimulated HSPA12B nuclear translocation and abrogated HSPA12B-promoted endothelial cell angiogenesis. Mechanistically, hypoxia induced an interaction between endothelial HSPA12B and YAP. ChIP assay showed that HSPA12B is a target gene of YAP/transcriptional enhanced associated domain 4 (TEAD4) and a coactivator in YAP-associated angiogenesis. In vivo studies using the MI model showed that endothelial cell-specific deficiency of HSPA12B (eHspa12b-/-) or YAP (eYap-/-) impaired angiogenesis and exacerbated cardiac dysfunction compared with WT mice. MI increased YAP expression and nuclear translocation in WT hearts but not eHspa12b-/- hearts. HSPA12B expression and nuclear translocation were upregulated in WT MI hearts but not eYap-/- MI myocardium. Our data demonstrate that endothelial HSPA12B is a target and coactivator for YAP/ TEAD4 and cooperates with YAP to regulate endothelial angiogenesis after MI.

β-Glucan derived from cell walls of Candida albicans is a potent immune modulator. It has been shown to induce trained immunity in monocytes via epigenetic and metabolic reprogramming and to protect from lethal sepsis if applied prior to infection. Since β-glucan-trained monocytes have not been classified within the system of mononuclear phagocytes we analyzed these cells metabolically, phenotypically and functionally with a focus on monocyte-to-macrophage differentiation and compared them with naïve monocytes and other types of monocyte-derived cells such as classically (M1) or alternatively (M2) activated macrophages and monocyte-derived dendritic cells (moDCs). We show that β-glucan inhibits spontaneous apoptosis of monocytes independent from autocrine or paracrine M-CSF release and stimulates monocyte differentiation into macrophages. β-Glucan-differentiated macrophages exhibit increased cell size and granularity and enhanced metabolic activity when compared to naïve monocytes. Although β-glucan-primed cells expressed markers of alternative activation and secreted higher levels of IL-10 after lipopolysaccharide (LPS), their capability to release pro-inflammatory cytokines and to kill bacteria was unaffected. Our data demonstrate that β-glucan priming induces a population of immune competent long-lived monocyte-derived macrophages that may be involved in immunoregulatory processes.

The β-1, 3 (d)-glucan (β-glucan) present in the cell wall of Candida albicans induces epigenetic changes in human monocytes resulting in primed macrophages exhibiting increased cytokine responsiveness to reinfection. This phenomenon is referred to as trained immunity or innate immune memory. However, whether β-glucan can reprogramme murine monocytes in vitro or induce lasting effects in vivo has yet to be elucidated. Thus, purified murine spleen-derived monocytes were primed with β-glucan in vitro and assessed for markers of differentiation and survival. Important macrophage cell markers during monocyte-to-macrophage differentiation were downregulated and survival enhanced due to partial inhibition of apoptosis. Increased survival and not the β-glucan training effect explained the elevated production of tumour necrosis factor-α (TNFα) and interleukin-6 (IL-6) induced by subsequent lipopolysaccharide (LPS) challenge. In vivo, 4 days after systemic administration of β-glucan, mice were more responsive to LPS challenge as shown by the increased serum levels of TNFα, IL-6 and IL-10, an effect shown to be short lived as enhanced cytokine production was lost by day 20. Here, we have characterised murine macrophages derived from β-glucan-primed monocytes based on their surface marker expression and for the first time provide evidence that the training effect of β-glucan in vivo declines within a 3-week period.

AS-1, the TIR/BB loop mimetic, plays a protective role in cardiac ischemia/reperfusion (I/R) but the molecular mechanism remains unclear. The muscle specific caveolin3 (Cav-3) and the caveolae have been found to be critical for cardioprotection. This study aimed to evaluate our hypothesis that caveolae and Cav-3 are essential for AS-1-induced cardioprotection against myocardial I/R injury. To address these issues, we analyzed the involvement of Cav-3 in AS-1 mediated cardioprotection both in vivo and in vitro. We demonstrate that AS-1 administration significantly decreased infarct size, improved cardiac function after myocardial I/R and modulated membrane caveolae and Cav-3 expression in the myocardium. For in vitro studies, AS-1 treatment prevented Cav-3 re-distribution induced by H/R injury. In contrast, disruption of caveolae by MCD treatment or Cav-3 knockdown abolished the protection against H/R-induced myocytes injury by AS-1. Our findings reveal that AS-1 attenuates myocardial I/R injury through caveolae and Cav-3 dependent mechanism.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Asthma is a heterogeneous disease whose etiology is poorly understood but is likely to involve innate responses to inhaled microbial components that are found in allergens. The influence of these components on pulmonary inflammation has been largely studied in the context of individual agonists, despite knowledge that they can have synergistic effects when used in combination. Here we have explored the effects of LPS and β-glucan, two commonly-encountered microbial agonists, on the pathogenesis of allergic and non-allergic respiratory responses to house dust mite allergen. Notably, sensitization with these micro-bial components in combination acted synergistically to promote robust neutrophilic inflammation, which involved both Dectin-1 and TLR-4. This pulmonary neutrophilic inflammation was corticosteroid-refractory, resembling that found in patients with severe asthma. Thus our results provide key new insights into how microbial components influence the development of respiratory pathology.