Analysis of chemical and genetic variability in wild hop (Humulus lupulus L.) populations of Kosovo.

Hops is an economically important species due to its diverse secondary metabolites and extensive use in the brewing and medicinal industries. Although hops is widely distributed in Kosovo, the chemical composition of its essential oils and genetic variability of wild populations remain understudied. Therefore, this study aimed to evaluate the chemical and genetic variability of Kosovo's wild hop population using essential oil constituents and microsatellite (simple sequence repeat - SSR) markers. Female hop inflorescences were collected from 21 wild populations in Kosovo. Essential oils were extracted from the dried plant material using a Clevenger apparatus. Chemical composition of the essential oils was analysed using GC-FID-MS. DNA was extracted from dried leaves, and 15 SSR markers were used for fragment analysis. The main constituents of the essential oil were myrcene, α-humulene, (E)-ß-farnesene, α-selinene, ß-selinene, and E-caryophyllene. Statistical analyses based on chemical composition of essential oils and SSR markers highlighted the low variability among populations and high variability within populations. These findings provide valuable insights for developing strategies for potential use and conservation of wild hop populations in Kosovo, laying the groundwork for future research and comparison with commercial cultivars to assess their breeding potential.

An Incidental Finding of a Massive Loculated Pericardial Effusion in a Patient Presenting With Inferior ST-Elevation Myocardial Infarction.

Pericardial effusion, commonly associated with malignancies such as lung, breast, and esophageal cancers through local extension, or leukemia, lymphoma, and melanoma via metastatic dissemination, is rarely observed in renal cell carcinoma (RCC). This report presents a rare case of a large loculated pericardial effusion in a 68-year-old male, potentially linked to RCC, who concurrently presented with an inferior wall ST-elevation myocardial infarction (STEMI). The patient, with a history of hypertension, hyperlipidemia, end-stage renal disease, coronary artery disease, and former smoking, exhibited symptoms including chest pain, diaphoresis, and shortness of breath, but no fever, chills, or night sweats. Diagnostic imaging revealed a significant pericardial effusion and a renal mass consistent with RCC, along with potential pulmonary metastases. Despite the complexity and high-risk nature of his condition, exacerbated by recent STEMI and dual antiplatelet therapy, a multidisciplinary approach was employed. This case emphasizes the need for careful management and tailored treatment strategies in patients with multiple coexisting conditions, highlighting the critical role of comprehensive diagnostic evaluation and collaborative care in improving patient outcomes.

Electrical excitability of cancer cells-CELEX model updated.

The normal functioning of every cell in the body depends on its bioelectric properties and many diseases are caused by genetic and/or epigenetic dysregulation of the underlying ion channels. Metastasis, the main cause of death from cancer, is a complex multi-stage process in which cells break away from a primary tumour, invade the surrounding tissues, enter the circulation by encountering a blood vessel and spread around the body, ultimately lodging in distant organs and reproliferating to form secondary tumours leading to devastating organ failure. Such cellular behaviours are well known to involve ion channels. The CELEX model offers a novel insight to metastasis where it is the electrical excitation of the cancer cells that is responsible for their aggressive and invasive behaviour. In turn, the hyperexcitability is underpinned by concomitant upregulation of functional voltage-gated sodium channels and downregulation of voltage-gated potassium channels. Here, we update the in vitro and in vivo evidence in favour of the CELEX model for carcinomas. The results are unequivocal for the sodium channel. The potassium channel arm is also broadly supported by existing evidence although these data are complicated by the impact of the channels on the membrane potential and consequent secondary effects. Finally, consistent with the CELEX model, we show (i) that carcinomas are indeed electrically excitable and capable of generating action potentials and (ii) that combination of a sodium channel inhibitor and a potassium channel opener can produce a strong, additive anti-invasive effect. We discuss the possible clinical implications of the CELEX model in managing cancer.

A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis.

Solid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.

Comparison of the effect of uric acid/albumin ratio on coronary slow flow with other inflammation-based markers.

Background: Many inflammation-based markers (IBMs) have been shown to be closely related to coronary slow flow (CSF), but the effect of the uric acid/albumin ratio (UAR) on CSF and its relationship with other IBMs are not clearly known. In this study, we aimed to compare the effects of UAR and other IBMs on CSF. Methods: After the exclusion criteria, 126 patients with CSF detected on coronary angiography and 126 subjects with normal coronary flow as the control group were included in the study. Results: UAR was determined as an independent predictor for CSF. In addition, the UAR was superior to other IBMs in detecting CSF (p < 0.05 for all). Conclusion: This study is the first to investigate the effect of UAR on CSF in comparison with other IBMs.

Ranolazine: a potential anti-metastatic drug targeting voltage-gated sodium channels.

BACKGROUND: Multi-faceted evidence from a range of cancers suggests strongly that de novo expression of voltage-gated sodium channels (VGSCs) plays a significant role in driving cancer cell invasiveness. Under hypoxic conditions, common to growing tumours, VGSCs develop a persistent current (INaP) which can be blocked selectively by ranolazine. METHODS: Several different carcinomas were examined. We used data from a range of experimental approaches relating to cellular invasiveness and metastasis. These were supplemented by survival data mined from cancer patients. RESULTS: In vitro, ranolazine inhibited invasiveness of cancer cells especially under hypoxia. In vivo, ranolazine suppressed the metastatic abilities of breast and prostate cancers and melanoma. These data were supported by a major retrospective epidemiological study on breast, colon and prostate cancer patients. This showed that risk of dying from cancer was reduced by ca.60% among those taking ranolazine, even if this started 4 years after the diagnosis. Ranolazine was also shown to reduce the adverse effects of chemotherapy on heart and brain. Furthermore, its anti-cancer effectiveness could be boosted by co-administration with other drugs. CONCLUSIONS: Ranolazine, alone or in combination with appropriate therapies, could be reformulated as a safe anti-metastatic drug offering many potential advantages over current systemic treatment modalities.

Lidocaine Inhibits Rat Prostate Cancer Cell Invasiveness and Voltage-Gated Sodium Channel Expression in Plasma Membrane.

There is increasing evidence, mostly from breast cancer, that use of local anaesthetics during surgery can inhibit disease recurrence by suppressing the motility of the cancer cells dependent on inherent voltage-gated sodium channels (VGSCs). Here, the possibility that lidocaine could affect cellular behaviours associated with metastasis was tested using the Dunning cell model of rat prostate cancer. Mostly, the strongly metastatic (VGSC-expressing) Mat-LyLu cells were used under both normoxic and hypoxic conditions. The weakly metastatic AT-2 cells served for comparison in some experiments. Lidocaine (1-500 µM) had no effect on cell viability or growth but suppressed Matrigel invasion dose dependently in both normoxia and hypoxia. Used as a control, tetrodotoxin produced similar effects. Exposure to hypoxia increased Nav1.7 mRNA expression but VGSCα protein level in plasma membrane was reduced. Lidocaine under both normoxia and hypoxia had no effect on Nav1.7 mRNA expression. VGSCα protein expression was suppressed by lidocaine under normoxia but no effect was seen in hypoxia. It is concluded that lidocaine can suppress prostate cancer invasiveness without effecting cellular growth or viability. Extended to the clinic, the results would suggest that use of lidocaine, and possibly other local anaesthetics, during surgery can suppress any tendency for post-operative progression of prostate cancer.

PREDICTION OF IRON DEFICIENCY IN CHILDREN USING EASY LABORATORY TOOLS.

Iron deficiency anemia is a common condition in children that can impair growth and development. This study aimed to evaluate the utility of easy, routinely available laboratory tests in predicting iron deficiency anemia. Medical records of 55 children (mean age 4.9±3.2 years) with laboratory evaluation of anemia were analyzed retrospectively. Parameters included complete blood count, serum iron, total iron binding capacity (TIBC), serum ferritin and transferrin saturation. Based on reference ranges, hemoglobin, hematocrit, serum ferritin and transferrin saturation were reduced below normal, indicating clear iron deficiency. Although within normal limits, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin and serum iron were close to lower limits, suggesting subtle deficiency. In contrast, red cell distribution width, platelet count, white blood cell count, TIBC and unsaturated iron binding capacity were unaffected. In conclusion, hemoglobin, and hematocrit from complete blood count, along with subtle changes in some of the red cell indices, can strongly suggest, iron deficiency anemia in children, Taking into consideration the increased body demand of iron in this age group with follow-up to ensure a desirable response, with less need for more advanced iron studies. These widely available, inexpensive tests may facilitate early detection and treatment of this common pediatric condition.

Calcitonin Gene-Related Peptide and Adrenomedullin Levels During Ictal and Interictal Periods in Patients With Migraine.

Background Peptides related to calcitonin gene-related peptide (CGRP) have been suggested to have a role in migraine. Adrenomedullin (AM) might be a candidate molecule because it is related to pain pathways in the peripheral and central nervous systems and uses the same receptors as CGRP. Methodology In this study, we examined the serum CGRP and AM levels during unprovoked ictal and interictal periods of 30 migraine patients as well as 25 healthy controls. Another focus of this study was on the association of CGRP and AM levels with clinical features. Results Mean serum AM levels were 15.80 pg/mL (11.91-21.43 pg/mL) in the ictal and 15.85 pg/mL (12.25-19.29 pg/mL) in the interictal periods in the migraine group and 13.36 pg/mL (10.84-17.18 pg/mL) in the control group. Mean serum CGRP levels were 2.93 pg/mL (2.45-3.90 pg/mL) in the ictal and 3.25 pg/mL (2.85-4.67 pg/mL) in the interictal periods in the migraine group and 3.03 pg/mL (2.48-3.80 pg/mL) in the control group. There were no statistical differences between ictal and/or interictal AM and CGRP levels (p = 0.558 and p = 0.054, respectively) which were also comparable with the results of the control group (p = 0.230, p = 0.295, p = 0.987, p = 0.139, respectively). Ictal serum CGRP and/or AM levels did not correlate with any of the reported clinical features. Conclusions Serum AM and CGRP levels are similar in interictal and unprovoked ictal periods in migraine patients and as well in controls. These results do not indicate that these molecules do not have a role in migraine pathophysiology. Considering the broad mechanisms of action of peptides in the CGRP family, further studies are needed in larger cohorts.

Resorbable membrane design: In vitro characterization of silver doped-hydroxyapatite-reinforced XG/PEI semi-IPN composite.

In this study, the production and characterization of silver-doped hydroxyapatite (AgHA) reinforced Xanthan gum (XG) and Polyethyleneimine (PEI) reinforced semi-interpenetrating polymer network (IPN) biocomposite, known to be used as bone cover material for therapeutic purposes in bone tissue, were performed. XG/PEI IPN films containing 2AgHA nanoparticles were produced by simultaneous condensation and ionic gelation. Characteristics of 2AgHA-XG/PEI nanocomposite film were evaluated by structural, morphological (SEM, XRD, FT-IR, TGA, TM, and Raman) and biological activity analysis (degradation, MTT, genotoxicity, and antimicrobial activity) techniques. In the physicochemical characterization, it was determined that 2AgHA nanoparticles were homogeneously dispersed in the XG/PEI-IPN membrane at high concentration and the thermal and mechanical stability of the formed film were high. The nanocomposites showed high antibacterial activity against Acinetobacter Baumannii (A.Baumannii), Staphylococcus aureus (S.aureus), and Streptococcus mutans (S.mutans). L929 exhibited good biocompatibility for fibroblast cells and was determined to support the formation of MCC cells. It was shown that a resorbable 2AgHA-XG/PEI composite material was obtained with a high degradation rate and 64% loss of mass at the end of the 7th day. Physico-chemically developed biocompatible and biodegradable XG-2AgHA/PEI nanocomposite semi-IPN films possessed an important potential for the treatment of defects in bone tissue as an easily applicable bone cover. Besides, it was noted that 2AgHA-XG/PEI biocomposite could increase cell viability, especially in dental-bone treatments for coating, filling, and occlusion.

Acquired Uterine Vascular Anomaly: Experience from a tertiary care centre in Pakistan.

Objectives: This study aimed to retrospectively review imaging findings and the outcomes of uterine artery embolisation (UAE) in symptomatic uterine vascular anomalies (UVA). Methods: This study included a total of 15 patients with acquired UVA admitted to the Aga Khan University Hospital in Karachi, Pakistan, from 2010 to 2020. These patients were evaluated using ultrasound, computed tomography and magnetic resonance imaging, either alone or in combination. All patients had a history of dilatation and curettage or uterine instrumentation and underwent angiography and embolisation of the uterine arteries. The primary outcome post embolisation was assessed clinically and/or in combination with ultrasound. Post-procedure pregnancies were also recorded. Results: Non-invasive imaging was abnormal in all patients; however, this pre-intervention imaging was unable to accurately classify the type of vascular anomaly, except in the case of a pseudoaneurysm. Conventional angiography showed uterine artery hyperaemia in six patients, arteriovenous malformation in seven patients and pseudoaneurysm in two patients. The technical success rate was 100% and no repeat embolisation was needed. The follow-up ultrasound in 12 patients revealed a resolution of the abnormal findings, while the remaining three were found to be normal on clinical follow-up. Seven patients (46.7%) had a normal pregnancy 15.7 months after the procedure (range: 4-28 months). Conclusions: UAE is a safe and effective management option for intractable severe bleeding in patients with UVA post instrumentation and it was found that the procedure does not impair future pregnancy.

Effect of psoas and gluteus medius muscles attenuation on hip fracture type.

INTRODUCTION: Sarcopenia is defined as a progressive loss of muscle mass and function with increased age. The measurement of muscle mass and attenuation on the axial computed tomography (CT) scan has been reported to be a good indicator for sarcopenia in previous literature. This study aimed to compare muscle mass between the intertrochanteric fracture and femoral neck fracture groups by accurately measuring muscle mass around the hip joint using a CT scan. METHODS: The cases were matched according to age and gender on a 1-to-1 basis. As a result, a total of 400 patients, 200 patients in each group with the same age and gender characteristics, were included in the study. At the disc of L4-L5 level, the cross-sectional area (CSA) of the psoas muscle was evaluated, and at the disc of L5-S1 level, the CSA of the psoas, iliacus and gluteus medius muscles were evaluated. In addition, attenuation was evaluated using the average Hounsfield Unit (HU) for the specific area. RESULTS: The mean age of 400 patients (262 females, 138 male) included in the study was 78.49 ± 7.67 years. It was observed that the mean HU values of the patients in the femoral neck fracture group were significantly higher than the intertrochanteric fracture group (p < 0.001, p = 0.008; respectively). At the same time, the mean HU values of the gluteus medius muscle were higher in the femoral neck fracture group (p < 0.001), but in contrast with the psoas muscle, the CSA values of gluteus medius muscle were significantly higher in the intertrochanteric fracture group (p = 0.017). CONCLUSIONS: Fatty degeneration of the psoas muscle among the muscles around the hip may affect the type of hip fracture. Elderly patients with strong psoas muscles may experience femoral neck fracture due to contraction and torsion during falling.

Voltage imaging reveals the dynamic electrical signatures of human breast cancer cells.

Cancer cells feature a resting membrane potential (Vm) that is depolarized compared to normal cells, and express active ionic conductances, which factor directly in their pathophysiological behavior. Despite similarities to 'excitable' tissues, relatively little is known about cancer cell Vm dynamics. Here high-throughput, cellular-resolution Vm imaging reveals that Vm fluctuates dynamically in several breast cancer cell lines compared to non-cancerous MCF-10A cells. We characterize Vm fluctuations of hundreds of human triple-negative breast cancer MDA-MB-231 cells. By quantifying their Dynamic Electrical Signatures (DESs) through an unsupervised machine-learning protocol, we identify four classes ranging from "noisy" to "blinking/waving". The Vm of MDA-MB-231 cells exhibits spontaneous, transient hyperpolarizations inhibited by the voltage-gated sodium channel blocker tetrodotoxin, and by calcium-activated potassium channel inhibitors apamin and iberiotoxin. The Vm of MCF-10A cells is comparatively static, but fluctuations increase following treatment with transforming growth factor-ß1, a canonical inducer of the epithelial-to-mesenchymal transition. These data suggest that the ability to generate Vm fluctuations may be a property of hybrid epithelial-mesenchymal cells or those originated from luminal progenitors.

Fabrication of mechanically advanced polydopamine decorated hydroxyapatite/polyvinyl alcohol bio-composite for biomedical applications: In-vitro physicochemical and biological evaluation.

In this study, polydopamine (PDA) coated hydroxyapatite (HA) reinforced polyvinyl alcohol (PVA) films were produced to be used in biomedical applications such as bone tissue regeneration. pDA is coated not only to prevent the agglomeration of HA when encountering interstitial fluids but also to strongly bind the PVA for the interaction between materials so that the mechanical performance becomes more stabilized. pDA was coated on the hydroxyapatite surface using a radical polymerization technique, and the reinforced PVA were produced with pDA-coated HA (pDA-HA/PVA) nanoparticles. Fundamental characteristic properties of pDA-HA/PVA nanocomposite films were examined by morphological/chemical (SEM-EDS), microstructural (XRD, Ft-IR, and Raman), thermodynamic (TGA and TM), mechanical performance (Vickers microhardness) and biological activity analysis (MTT, genotoxicity and antimicrobial efficacy investigations). Physicochemical analysis showed that all the samples studied exhibited homogeneous mineral distributions through the main structures. According to TGA, TMA and hardness tests, the new composite structure possessed higher mechanical properties than neat PVA. Further, pDA-HA/PVA nanocomposites exhibited high antibacterial capacities against Acinetobacter Baumannii (A.Baumannii), Staphylococcus aureus (S. aureus), and Streptococcus mutans (S.mutans). Moreover, the new nanocomposites were noted to present good biocompatibility for fibroblast (L929) cells and to support remarkably MCS cells. All in all, this comprehensive work shows that the thermo-mechanically improved pDA-HA/PVA films will increase the application fields of PVA in biomedical fields especially tooth-bone treatments for coating, filling, or occlusion purposes.

Combinatorial Therapy of Cancer: Possible Advantages of Involving Modulators of Ionic Mechanisms.

Cancer is a global health problem that 1 in 2-3 people can expect to experience during their lifetime. Several different modalities exist for cancer management, but all of these suffer from significant shortcomings in both diagnosis and therapy. Apart from developing completely new therapies, a viable way forward is to improve the efficacy of the existing modalities. One way is to combine these with each other or with other complementary approaches. An emerging latter approach is derived from ionic mechanisms, mainly ion channels and exchangers. We evaluate the evidence for this systematically for the main treatment methods: surgery, chemotherapy, radiotherapy and targeted therapies (including monoclonal antibodies, steroid hormones, tyrosine kinase inhibitors and immunotherapy). In surgery, the possible systemic use of local anesthetics to suppress subsequent relapse is still being discussed. For all the other methods, there is significant positive evidence for several cancers and a range of modulators of ionic mechanisms. This applies also to some of the undesirable side effects of the treatments. In chemotherapy, for example, there is evidence for co-treatment with modulators of the potassium channel (Kv11.1), pH regulation (sodium-hydrogen exchanger) and Na+-K+-ATPase (digoxin). Voltage-gated sodium channels, shown previously to promote metastasis, appear to be particularly useful for co-targeting with inhibitors of tyrosine kinases, especially epidermal growth factor. It is concluded that combining current orthodox treatment modalities with modulators of ionic mechanisms can produce beneficial effects including (i) making the treatment more effective, e.g., by lowering doses; (ii) avoiding the onset of resistance to therapy; (iii) reducing undesirable side effects. However, in many cases, prospective clinical trials are needed to put the findings firmly into clinical context.

Anti-invasive effects of minoxidil on human breast cancer cells: combination with ranolazine.

A plethora of ion channels have been shown to be involved systemically in the pathophysiology of cancer and ion channel blockers can produce anti-metastatic effects. However, although ion channels are known to frequently function in concerted action, little is known about possible combined effects of ion channel modulators on metastatic cell behaviour. Here, we investigated functional consequences of pharmacologically modulating ATP-gated potassium (KATP) channel and voltage-gated sodium channel (VGSC) activities individually and in combination. Two triple-negative human breast cancer cell lines were used: MDA-MB-231 and MDA-MB-468, the latter mainly for comparison. Most experiments were carried out on hypoxic cells. Electrophysiological effects were studied by whole-cell patch clamp recording. Minoxidil (a KATP channel opener) and ranolazine (a blocker of the VGSC persistent current) had no effect on cell viability and proliferation, alone or in combination. In contrast, invasion was significantly reduced in a dose-dependent manner by clinical concentrations of minoxidil and ranolazine. Combining the two drugs produced significant additive effects at concentrations as low as 0.625 µM ranolazine and 2.5 µM minoxidil. Electrophysiologically, acute application of minoxidil shifted VGSC steady-state inactivation to more hyperpolarised potentials and slowed recovery from inactivation, consistent with inhibition of VGSC activation. We concluded (i) that clinically relevant doses of minoxidil and ranolazine individually could inhibit cellular invasiveness dose dependently and (ii) that their combination was additionally effective. Accordingly, ranolazine, minoxidil and their combination may be repurposed as novel anti-metastatic agents.

Ion Transporting Proteins and Cancer: Progress and Perspectives.

Ion transporting proteins (ITPs) comprise a wide range of ion channels, exchangers, pumps and ionotropic receptors many of which are expressed in tumours and contribute dynamically to the different components and stages of the complex cancer process, from initiation to metastasis. In this promising major field of biomedical research, several candidate ITPs have emerged as clinically viable. Here, we consider a series of general issues concerning the oncological potential of ITPs focusing on voltage-gated sodium channels as a 'case study'. First, we outline some key properties of 'cancer' as a whole. These include epigenetics, stemness, metastasis, heterogeneity, neuronal characteristics and bioelectricity. Cancer specificity of ITP expression is evaluated in relation to tissue restriction, splice variance, functional specificity and macro-molecular complexing. As regards clinical potential, diagnostics is covered with emphasis on enabling early detection. For therapeutics, we deal with molecular approaches, drug repurposing and combinations. Importantly, we emphasise the need for carefully designed clinical trials. We highlight also the area of 'social responsibility' and the need to involve the public (cancer patients and healthy individuals) in the work of cancer research professionals as well as clinicians. In advising patients how best to manage cancer, and live with it, we offer the following four principles: Awareness and prevention, early detection, specialist, integrated care, and psychological support. Finally, we highlight four key prerequisites for commercialisation of ITP-based technologies against cancer. We conclude that ITPs offer significant potential as regards both understanding the intricacies of the complex process of cancer and for developing much needed novel therapies.

Integrative Management of Pancreatic Cancer (PDAC): Emerging Complementary Agents and Modalities.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. The standard first-line treatment for PDAC is gemcitabine chemotherapy which, unfortunately, offers only limited chance of a lasting cure. This review further evaluates the hypothesis that the effectiveness of gemcitabine can be improved by combining it with evidence-based complementary measures. Previously, supported by clinical trial data, we suggested that a number of dietary factors and nutraceuticals can be integrated with gemcitabine therapy. Here, we evaluate a further 10 agents for which no clinical trials have (yet) been carried out but there are promising data from in vivo and/or in vitro studies including experiments involving combined treatments with gemcitabine. Two groups of complementary agents are considered: Dietary factors (resveratrol, epigallocatechin gallate, vitamin B9, capsaicin, quercetin and sulforaphane) and nutraceutical agents (artemisinin, garcinol, thymoquinone and emodin). In addition, we identified seven promising agents for which there is currently only basic (mostly in vitro) data. Finally, as a special case of combination therapy, we highlighted synergistic drug combinations involving gemcitabine with "repurposed" aspirin or metformin. We conclude overall that integrated management of PDAC currently is likely to produce the best outcome for patients and for this a wide range of complementary measures is available.