Immunohistochemical evaluation of osteopontin expression in triple-negative breast cancer.

Introduction: Triple-negative breast cancer (TNBC) is associated with lack of expression of estrogen and progesterone receptors and HER2 and is the subgroup of breast cancers with the worst prognosis. Osteopontin is a phosphorylated glycoprotein whose overexpression may occur in pathological states such as cancers. The main purpose of our study was to evaluate the immunohistochemical expression of osteopontin in connection with the analysis of recognized clinical and pathological prognostic factors in primary sites of TNBC with and without lymph node metastases. Material and methods: The immunohistochemical evaluation of osteopontin expression in 35 women with TNBC, chosen from a group of 726 patients, was performed. The material came from the excisional biopsies of primary breast cancers and total mastectomies. Results: All patients showed expression of osteopontin, in most cases the expression of osteopontin rated at [+] (57.1%) and [++] (42.9%). Our study analyzed the relationship between the expression of osteopontin and traditional prognostic markers, such as the tumor grade, size, and lymph node involvement. We found a strong relationship only between the expression of osteopontin and the presence of lymph node metastases (p ≤ 0.0001). 93% of patients for whom the expression of osteopontin was determined at [++] had metastasis to lymph nodes and, for comparison, only 15% of women for whom the expression of osteopontin was rated at [+] showed the presence of metastases in the lymphatic nodes. Conclusions: There is a correlation between osteopontin expression and the presence of lymph node metastases in TNBC, suggesting that osteopontin plays an important role in the invasiveness of TNBC.

How A Patient with Resectable or Borderline Resectable Pancreatic Cancer should Be Treated-A Comprehensive Review.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high morbidity and mortality in which long-term survival rates remain disastrous. Surgical resection is the only potentially curable treatment for early pancreatic cancer; however, the right patient qualification is crucial for optimizing treatment outcomes. With the rapid development of radiographic and surgical techniques, resectability decisions are made by a multidisciplinary team. Upfront surgery (Up-S) can improve the survival of patients with potentially resectable disease with the support of adjuvant therapy (AT). However, early recurrences are quite common due to the often-undetectable micrometastases occurring before surgery. Adopted by international consensus in 2017, the standardization of the definitions of resectable PDAC (R-PDAC) and borderline resectable PDAC (BR-PDAC) disease was necessary to enable accurate interpretation of study results and define which patients could benefit from neoadjuvant therapy (NAT). NAT is expected to improve the resection rate with a negative margin to provide significant local control and eliminate micrometastases to prolong survival. Providing information about optimal sequential multimodal NAT seems to be key for future studies. This article presents a multidisciplinary concept for the therapeutic management of patients with R-PDAC and BR-PDAC based on current knowledge and our own experience.

Evaluation of Nutritional Status and the Impact of Nutritional Treatment in Patients with Pancreatic Cancer.

Patients with pancreatic cancer who develop irreversible cancer cachexia have a life expectancy of less than 3 months. Therefore, it is extremely important to evaluate the patient's nutritional status as early as possible and to implement an appropriate nutritional intervention in order to reduce the risk of further weight loss and/or muscle loss, which affect the outcomes of cancer treatment and the correct nutritional treatment in patients with pancreatic cancer. A literature review was performed by using the PubMed and Cochrane quick search methodology. The main purpose of this review was to present the current approach to nutritional treatment in pancreatic cancer. The review included publications, most of which concerned clinical nutrition as part of the phase of treatment of patients with pancreatic cancer, nutritional and metabolic disorders in pancreatic cancer, and the period after pancreatic resection. Some of the publications concerned various nutritional interventions in patients with pancreatic cancer undergoing chemotherapy or surgical treatment (nutritional support before surgery, after surgery, or during palliative treatment). There is an unmet need for integrated nutritional therapy as a key part of the comprehensive care process for PC patients. Nutritional counseling is the first line of nutritional treatment for malnourished cancer patients, but pancreatic enzyme replacement therapy also constitutes the cornerstone of nutritional treatment for relieving symptoms of indigestion and maintaining or improving nutritional status.

Rare Non-Neuroendocrine Pancreatic Tumours.

The most common tumour of the pancreas is ductal adenocarcinoma (PDAC). It remains one of the most lethal non-neuroendocrine solid tumours despite the use of a multi-approach strategy. Other, less-common neoplasms, which are responsible for 15% of pancreatic lesions, differ in treatment and prognosis. Due to the low incidence rate, there is a lack of information about the rarest pancreatic tumours. In this review, we described six rare pancreatic tumours: intraductal papillary mucinous neoplasm (IPMN), mucinous cystadenoma (MCN), serous cystic neoplasm (SCN), acinar cell carcinoma (ACC), solid pseudopapillary neoplasm (SPN) and pancreatoblastoma (PB). We distinguished their epidemiology, clinical and gross features, covered the newest reports about courses of treatment and systematised differential diagnoses. Although the most common pancreatic tumour, PDAC, has the highest malignant potential, it is still essential to properly classify and differentiate less-common lesions. It is vital to continue the search for new biomarkers, genetic mutations and the development of more specific biochemical tests for determining malignancy in rare pancreatic neoplasms.

New Treatment Options in Metastatic Pancreatic Cancer.

Pancreatic cancer (PC) is the seventh leading cause of cancer death across the world. Poor prognosis of PC is associated with several factors, such as diagnosis at an advanced stage, early distant metastases, and remarkable resistance to most conventional treatment options. The pathogenesis of PC seems to be significantly more complicated than originally assumed, and findings in other solid tumours cannot be extrapolated to this malignancy. To develop effective treatment schemes prolonging patient survival, a multidirectional approach encompassing different aspects of the cancer is needed. Particular directions have been established; however, further studies bringing them all together and connecting the strengths of each therapy are needed. This review summarises the current literature and provides an overview of new or emerging therapeutic strategies for the more effective management of metastatic PC.

Quality of Life in Patients with Pancreatic Cancer-A Literature Review.

Pancreatic cancer is the malignant disease with the highest mortality rate, and it ranks third in the world after lung and colon cancer. Identified factors that increase the risk of developing pancreatic cancer include chronic pancreatitis, radiation therapy to the pancreatic area due to another cancer, diabetes mellitus, obesity, smoking, and age. The objective of this study was to present the current state of knowledge on the quality of life of patients diagnosed with pancreatic cancer, factors that determine QoL, and ways of coping with the disease. The low curability and low survival rates of pancreatic cancer significantly affect the quality of life of patients, often in the form of significant deterioration, especially in terms of mental changes, cognitive functions, and coping with the disease. Cognitive decline with comorbid depression is also typical for patients with this type of cancer. Research has shown that the health-related quality of life of patients with pancreatic cancer is low, so further research is needed to improve the situation in this area.

Cancer-associated inflammation: pathophysiology and clinical significance.

PURPOSE: Cancer cells, despite stemming from the own cells of their host, usually elicit an immune response. This response usually enables elimination of cancer at its earliest stages. However, some tumors develop mechanisms of escaping immune destruction and even profiting from tumor-derived inflammation. METHODS: We summarized the roles of different immune cell populations in various processes associated with cancer progression and possible methods of reshaping tumor-associated inflammation to increase the efficacy of cancer therapy. RESULTS: Changes in various signaling pathways result in attraction of immunosuppressive, pro-tumorigenic cells, such as myeloid-derived suppressor cells, tumor-associated macrophages, and neutrophils, while at the same time suppressing the activity of lymphocytes, which have the potential of destroying cancer cells. These changes promote tumor progression by increasing angiogenesis and growth, accelerating metastasis, and impairing drug delivery to the tumor site. CONCLUSION: Due to its multi-faceted role in cancer, tumor-associated inflammation can serve as a valuable therapy target. By increasing it, whether through decreasing overall immunosuppression with immune checkpoint inhibitor therapy or through more specific methods, such as cancer vaccines, oncolytic viruses, or chimeric antigen receptor T cells, cancer-derived immunosuppression can be overcome, resulting in immune system destroying cancer cells. Even changes occurring in the microbiota can influence the shape of antitumor response, which could provide new attractive diagnostic or therapeutic methods. Interestingly, also decreasing the distorted tumor-associated inflammation with non-steroidal anti-inflammatory drugs can lead to positive outcomes.

Diabetes Mellitus and Pancreatic Ductal Adenocarcinoma-Prevalence, Clinicopathological Variables, and Clinical Outcomes.

BACKGROUND: pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer-related deaths with increasing incidence and link to the onset of diabetes mellitus (DM). The aim of this study is to describe the prevalence of DM among patients with the diagnosis of PDAC, analyse the association between the occurrence of DM and clinicopathological factors, and detect variables influencing overall survival. METHODS: a retrospective analysis of medical records was performed. The patients were divided into non-DM (n = 101) and DM (n = 74) groups. Statistical analysis with the usage of appropriate tests was conducted. RESULTS: Patients in the groups of DM and NODM had significantly longer median OS than the non-DM group. Nodal involvement, tumour location, level of CEA, CRP and CRP/lymphocytes ratio were significantly associated with OS among patients with any type of DM. Neutropenia was less frequently observed in the DM group. CONCLUSIONS: DM is prevalent among patients with pancreatic cancer. In our study, patients with DM receiving palliative chemotherapy had significantly higher median OS than those without DM. The increased comprehension of the mechanisms of the relationship between DM and pancreatic cancer needs further research, which might provide avenues for the development of novel preventive and therapeutic strategies.

Current State of Knowledge on the Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer Treatment: Approaches, Efficacy, and Challenges.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with limited treatment options. Recently, there has been a growing interest in immunotherapy with immune checkpoint inhibitors (ICIs) in TNBC, leading to extensive preclinical and clinical research. This review summarizes the current state of knowledge on ICIs efficacy and their predictive markers in TNBC and highlights the areas where the data are still limited. Currently, the only approved ICI-based regimen for TNBC is pembrolizumab with chemotherapy. Its advantage over chemotherapy alone was confirmed for non-metastatic TNBC regardless of programmed death-ligand 1 (PD-L1) expression (KEYNOTE-522) and for metastatic, PD-L1-positive TNBC (KEYNOTE-355). Pembrolizumab's efficacy was also evaluated in monotherapy, or in combination with niraparib and radiation therapy, showing potential efficacy and acceptable safety profile in phase 2 clinical trials. Atezolizumab + nab-paclitaxel increased the overall survival (OS) over placebo + nab-paclitaxel in early TNBC, regardless of PD-L1 status (IMpassion031). In IMpassion130 (untreated, advanced TNBC), the OS improvement was not statistically significant in the intention-to-treat population but clinically meaningful in the PD-L1 positive cohort. The durvalumab-anthracycline combination showed an increased response durability over placebo anthracycline in early TNBC (GeparNuevo). Several phase 1 clinical trials also showed a potential efficacy of atezolizumab and avelumab monotherapy in metastatic TNBC. ICIs appear to be applicable in both neoadjuvant and adjuvant settings, and are both pretreated and previously untreated patients. Further research is necessary to determine the most beneficial drug combinations and optimize patient selection. It is essential to identify the predictive markers for ICIs and factors affecting their expression.

Medullary breast cancer is a predominantly triple-negative breast cancer - histopathological analysis and comparison with invasive ductal breast cancer.

Introduction: Medullary breast cancer (MdBC) is an uncommon type of breast cancer representing 1-7% of all cases. It is characterized by the occurrence of many histopathological features associated with a high grade of malignancy. Material and methods: Twelve MdBCs chosen from a group of 1,122 women suffering from invasive breast cancer were analyzed. Histopathological examination and analysis of a basic molecular profile, i.e. estrogen (ER), progesterone (PR) and HER2 receptor expression, and their comparison with invasive ductal breast cancer (IDC), were performed. Results: MdBC accounted for 1.07% of all analyzed invasive breast cancer patients. All patients were female, with an average age of 58.54 years. The MdBC group exhibited a larger median tumor diameter (2.05 vs. 1.89 cm), although ≥ T2 tumors comprised 42% vs. 51% for IDCs. Women without regional lymph node involvement (pN0) (83%) formed the largest group. There was a statistically significant difference in the presence of nodal involvement between the studied groups (p < 0.001). Based on the histological grade of malignancy, the majority of MdBC comprised grade II tumors (G2) (93%). In general, MdBC showed statistically higher histologic grade (G1-G3) than IDC (p = 0.003). The 5-year overall survival rate of MdBC patients was 91%. Most MdBCs (92%) were triple-negative, whereas the remaining 8% were HER2 positive. Conclusions: MdBC presented at a younger age than IDC, had a higher histological grade, larger median size and less frequent regional lymph node involvement. Most MdBCs were triple-negative, whereas IDCs were predominantly luminal. Despite numerous aggressive pathological features of MdBC, its clinical outcome and overall prognosis are favorable.

Pulmonary blastoma in a pregnant woman: a case report and brief review of the literature.

BACKGROUND: Pulmonary blastoma (PB) comprises a rare heterogeneous group of lung tumours typically containing immature epithelial and mesenchymal structures that imitate the embryonic lung tissue and extremely rarely occurs during pregnancy. Although cough and haemoptysis are the most common PB symptoms, they usually indicate other serious pregnancy-related complications. CASE PRESENTATION: The article presents the unusual case of a 22-year-old pregnant woman diagnosed with PB during pregnancy. CONCLUSIONS: PB is characterized by poor prognosis and patients' outcome relies on a rapid diagnosis. Surgery remains the most common and effective treatment. Due to the extreme rarity, the literature contains only single mentions of PB in pregnancy, thus its impact on the course of pregnancy and the developing fetus remains unknown.

Adenylate kinases of thermophiles Aquifex aeolicus and Geobacillus stearothermophilus: biochemical and kinetic studies.

Adenylate kinases (AK) play a pivotal role in the regulation of cellular energy. The aim of our work was to achieve the overproduction and purification of AKs from two groups of bacteria and to determine, for the first time, the comprehensive biochemical and kinetic properties of adenylate kinase from Gram-negative Aquifex aeolicus (AKaq) and Gram-positive Geobacillus stearothermophilus (AKst). Therefore we determined KM and Vmax values, and the effects of temperature, pH, metal ions, donors of the phosphate groups and inhibitor Ap5A for both thermophilic AKs. The kinetic studies indicate that both AKs exhibit significantly higher affinity for substrates with the pyrophosphate group than for adenosine monophosphate. AK activation by Mg2+ and Mn2+ revealed that both ions are efficient in the synthesis of adenosine diphosphate and adenosine triphosphate; however, Mn2+ ions at 0.2-2.0 mmol/L concentration were more efficient in the activation of the ATP synthesis than Mg2+ ions. Our research demonstrates that zinc ions inhibit the activity of enzymes in both directions, while Ap5A at a concentration of 10 µmol/L and 50 µmol/L inhibited both enzymes with a different efficiency. Sigmoid-like kinetics were detected at high ATP concentrations not balanced by Mg2+, suggesting the allosteric effect of ATP for both bacterial AKs.

Biological Inspirations: Iron Complexes Mimicking the Catechol Dioxygenases.

Within the broad group of Fe non-heme oxidases, our attention was focused on the catechol 1,2- and 2,3-dioxygenases, which catalyze the oxidative cleavage of aromatic rings. A large group of Fe complexes with N/O ligands, ranging from N3 to N2O2S, was developed to mimic the activity of these enzymes. The Fe complexes discussed in this work can mimic the intradiol/extradiol catechol dioxygenase reaction mechanism. Electronic effects of the substituents in the ligand affect the Lewis acidity of the Fe center, increasing the ability to activate dioxygen and enhancing the catalytic activity of the discussed biomimetic complexes. The ligand architecture, the geometric isomers of the complexes, and the substituent steric effects significantly affect the ability to bind the substrate in a monodentate and bidentate manner. The substrate binding mode determines the preferred mechanism and, consequently, the main conversion products. The preferred mechanism of action can also be affected by the solvents and their ability to form the stable complexes with the Fe center. The electrostatic interactions of micellar media, similar to SDS, also control the intradiol/extradiol mechanisms of the catechol conversion by discussed biomimetics.

Assessing the Interactions of Statins with Human Adenylate Kinase Isoenzyme 1: Fluorescence and Enzyme Kinetic Studies.

Statins are the most effective cholesterol-lowering drugs. They also exert many pleiotropic effects, including anti-cancer and cardio- and neuro-protective. Numerous nano-sized drug delivery systems were developed to enhance the therapeutic potential of statins. Studies on possible interactions between statins and human proteins could provide a deeper insight into the pleiotropic and adverse effects of these drugs. Adenylate kinase (AK) was found to regulate HDL endocytosis, cellular metabolism, cardiovascular function and neurodegeneration. In this work, we investigated interactions between human adenylate kinase isoenzyme 1 (hAK1) and atorvastatin (AVS), fluvastatin (FVS), pravastatin (PVS), rosuvastatin (RVS) and simvastatin (SVS) with fluorescence spectroscopy. The tested statins quenched the intrinsic fluorescence of hAK1 by creating stable hAK1-statin complexes with the binding constants of the order of 104 M-1. The enzyme kinetic studies revealed that statins inhibited hAK1 with significantly different efficiencies, in a noncompetitive manner. Simvastatin inhibited hAK1 with the highest yield comparable to that reported for diadenosine pentaphosphate, the only known hAK1 inhibitor. The determined AK sensitivity to statins differed markedly between short and long type AKs, suggesting an essential role of the LID domain in the AK inhibition. Our studies might open new horizons for the development of new modulators of short type AKs.

Biochemical Characterization of Recombinant UDPG-Dependent IAA Glucosyltransferase from Maize (Zea mays).

Here, we report a biochemical characterization of recombinant maize indole-3-acetyl-ß-d-glucose (IAGlc) synthase which glucosylates indole-3-acetic acid (IAA) and thus abolishes its auxinic activity affecting plant hormonal homeostasis. Substrate specificity analysis revealed that IAA is a preferred substrate of IAGlc synthase; however, the enzyme can also glucosylate indole-3-butyric acid and indole-3-propionic acid with the relative activity of 66% and 49.7%, respectively. KM values determined for IAA and UDP glucose are 0.8 and 0.7 mM, respectively. 2,4-Dichlorophenoxyacetic acid is a competitive inhibitor of the synthase and causes a 1.5-fold decrease in the enzyme affinity towards IAA, with the Ki value determined as 117 µM, while IAA-Asp acts as an activator of the synthase. Two sugar-phosphate compounds, ATP and glucose-1-phosphate, have a unique effect on the enzyme by acting as activators at low concentrations and showing inhibitory effect at higher concentrations (above 0.6 and 4 mM for ATP and glucose-1-phosphate, respectively). Results of molecular docking revealed that both compounds can bind to the PSPG (plant secondary product glycosyltransferase) motif of IAGlc synthase; however, there are also different potential binding sites present in the enzyme. We postulate that IAGlc synthase may contain more than one binding site for ATP and glucose-1-phosphate as reflected in its activity modulation.

Improved understanding of gastrointestinal stromal tumors biology as a step for developing new diagnostic and therapeutic schemes.

A gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract, with an estimated incidence of 10-15 per 1 million per year. While preparing holistic care for patients with GIST diagnosis, scientists might face several difficulties - insufficient risk stratification, acquired or secondary resistance to imatinib, or the need for an exceptional therapy method associated with wild-type tumors. This review summarizes recent advances associated with GIST biology that might enhance diagnostic and therapeutic strategies. New molecules might be incorporated into risk stratification schemes due to their proven association with outcomes; however, further research is required. Therapies based on the significant role of angiogenesis, immunology, and neural origin in the GIST biology could become a valuable enhancement of currently implemented treatment schemes. Generating miRNA networks that would predict miRNA regulatory functions is a promising approach that might help in better selection of potential biomarkers and therapeutical targets in cancer, including GISTs.

The complexity of tumour angiogenesis based on recently described molecules.

Tumour angiogenesis is a crucial factor associated with tumour growth, progression, and metastasis. The whole process is the result of an interaction between a wide range of different molecules, influencing each other. Herein we summarize novel discoveries related to the less known angiogenic molecules such as galectins, pentraxin-3, Ral-interacting protein of 76 kDa (RLIP76), long non-coding RNAs (lncRNAs), B7-H3, and delta-like ligand-4 (DLL-4) and their role in the process of tumour angiogenesis. These molecules influence the most important molecular pathways involved in the formation of blood vessels in cancer, including the vascular endothelial growth factor (VEGF)-vascular endothelial growth factor receptor interaction (VEGFR), HIF1-a activation, or PI3K/Akt/mTOR and JAK-STAT signalling pathways. Increased expression of galectins, RLIP76, and B7H3 has been proven in several malignancies. Pentraxin-3, which appears to inhibit tumour angiogenesis, shows reduced expression in tumour tissues. Anti-angiogenic treatment based mainly on VEGF inhibition has proved to be of limited effectiveness, leading to the development of drug resistance. The newly discovered molecules are of great interest as a potential source of new anti-cancer therapies. Their role as targets for new drugs and as prognostic markers in neoplasms is discussed in this review.

Histopathological analysis of mucinous breast cancer subtypes and comparison with invasive carcinoma of no special type.

Mucinous breast cancer (MBC) is a rare histological type of breast cancer characterized primarily by mucin's production and extracellular presence. MBC is usually associated with a better prognosis than other invasive breast neoplasms. Because of the low prevalence, MBC biology is not well understood. The aim of the present study was to introduce the last 2-year experience regarding MBC pathological diagnostics in our clinical center and comparison of the obtained data with invasive breast carcinoma of no special type (NST) comprising the most common invasive breast cancer. We identified 24 MBC cases representing 3.09% of all 766 invasive breast cancers, including 15 cases of pure type and 9 mixed MBCs. The median MBC patients' age at presentation was 65.5 years. Compared to NST, MBC presented a higher T stage with a statistically larger tumor median size, although lower regional lymph node involvement, tumor histological grade and TNM stage. MBC is a rare type of breast cancer, accounting for about 4% of all diagnosed breast cancers. Our findings are consistent with those published in recent years and show significant differences between MBC and NST cancer patients and also highlight differences between pure and mixed MBC, emphasizing the essence of their differentiation. MBC is associated with a better long-term prognosis than NST and is characterized by the less aggressive biological behavior expressed through favorable clinicopathologic features in terms of tumor grade, regional lymph node involvement and hormone receptor status.

A tandem motif-based and structural approach can identify hidden functional phosphodiesterases.

Cyclic nucleotide monophosphates (cNMPs) are increasingly recognized as essential signaling molecules governing many physiological and developmental processes in prokaryotes and eukaryotes. Degradation of cNMPs is as important as their generation because it offers the capability for transient and dynamic cellular level regulation but unlike their generating enzymes, the degrading enzymes, cyclic nucleotide phosphodiesterases (PDEs) are somewhat elusive in higher plants. Based on sequence analysis and structural properties of canonical PDE catalytic centers, we have developed a consensus sequence search motif and used it to identify candidate PDEs. One of these is an Arabidopsis thaliana K+-Uptake Permease (AtKUP5). Structural and molecular docking analysis revealed that the identified PDE domain occupies the C-terminal of this protein forming a solvent-exposed distinctive pocket that can spatially accommodate the cyclic adenosine monophosphate (cAMP) substrate and importantly, cAMP assumes a binding pose that is favorable for interactions with the key amino acids in the consensus motif. PDE activity was confirmed by the sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Notably, this activity was stimulated by the Ca2+/CaM complex, the binding of which to the PDE center was confirmed by surface plasmon resonance (SPR). Since AtKUP5 also has adenylate cyclase (AC) activity that is essential for K+ transport, we propose that this dual moonlighting AC-PDE architecture, offers modulatory roles that afford intricate intramolecular regulation of cAMP levels thereby enabling fine-tuning of cAMP signaling in K+ homeostasis.