The right to deduct the input tax with no option to correct the tax return owing to the expiry of the tax obligation

Podatnik nie może legalnie stosować poglądu wynikającego z interpretacji prawa krajowego, który zaprzeczałby istocie podatku od wartości dodanej wynikającej z prawa UE i nie odpowiadałby zasadniczym jego cechom. Teza, jakoby podatnik, mając zamiar pomniejszyć podatek należny o podatek naliczony, musiałby ponownie (po raz drugi) wykazać podatek należny, byłaby równoznaczna z zastosowaniem odmiennej stawki podatku niż ta, którą stosują inni podatnicy dokonujący analogicznych dostaw. Stosowanie zróżnicowanych stawek w stosunku do tych samych czynności – dostaw energii elektrycznej i gazu ziemnego spowodowałoby ponadto zakłócenie konkurencji, biorąc pod uwagę fakt, że inni przedsiębiorcy z tytułu tych samych czynności stosują stawkę 23%. Możliwości selektywnego zastosowania stawki niższej w stosunku do innych podmiotów przy założeniu, że podatnik powinien opodatkować dokonane czynności de facto według stawki 46%, kłóciłaby się z regułami konkurowania podmiotów gospodarczych na tych samych zasadach.The taxpayer must not legally apply a view, ensuing from interpretation of the national laws, which would oppose the essence of the value-added tax under the EU laws and would not be correspondent with its basic characteristics. The argument that, in an intent to have the output tax reduced by the input tax, the taxpayer would have to disclose the output tax once again, would be tantamount to application of a tax rate different to the one applied by other taxpayers who perform analogous supplies. Application of diverse rates to the same actions–supplies of electricity and natural gas–would moreover result in distorted competition, taking into account that the other entrepreneurs use the rate of 23% in respect of the same actions. A possibility to selectively apply a lower rate, in the context of those used by the other entities and given the assumption that the taxpayer ought to tax the actions performed, de facto, at the rate 46%, would conflict with the rules of competition between economic entities under the same rules

Prawo do odliczenia podatku naliczonego w przypadku braku możliwości korekty deklaracji z uwagi na przedawnienie zobowiązania podatkowego

Podatnik nie może legalnie stosować poglądu wynikającego z interpretacji prawa krajowego, który zaprzeczałby istocie podatku od wartości dodanej wynikającej z prawa UE i nie odpowiadałby zasadniczym jego cechom. Teza, jakoby podatnik, mając zamiar pomniejszyć podatek należny o podatek naliczony, musiałby ponownie (po raz drugi) wykazać podatek należny, byłaby równoznaczna z zastosowaniem odmiennej stawki podatku niż ta, którą stosują inni podatnicy dokonujący analogicznych dostaw. Stosowanie zróżnicowanych stawek w stosunku do tych samych czynności – dostaw energii elektrycznej i gazu ziemnego spowodowałoby ponadto zakłócenie konkurencji, biorąc pod uwagę fakt, że inni przedsiębiorcy z tytułu tych samych czynności stosują stawkę 23%. Możliwości selektywnego zastosowania stawki niższej w stosunku do innych podmiotów przy założeniu, że podatnik powinien opodatkować dokonane czynności de facto według stawki 46%, kłóciłaby się z regułami konkurowania podmiotów gospodarczych na tych samych zasadach. </jats:p

Stress Perception and Coping Strategies of Students on Both Sides of the EU&rsquo;s Eastern Border during the COVID-19 Pandemic

The aim of the study was to compare the perception of stress and the characteristic coping-strategies among students in the context of the different anti-pandemic measures taken in Belarus, Poland, and the Russian exclave of Kaliningrad. A cross-sectional online survey using standardized questionnaires (Perceived Stress Scale&mdash;PSS-10 and Brief-COPE&mdash;Mini-COPE inventory) was conducted among 3113 students of seven universities in three neighboring regions on both sides of the eastern border of the EU. The groups that are the most prone to stress are the Polish and Russians students. Among the students from Belarus, 122 (13.7%) have high levels of stress symptoms. Among the respondents from Poland&mdash;238 (19.4%), and 191 (19.2%) from Kaliningrad have high levels of stress, respectively. The different approaches of the authorities to the COVID-19 pandemic diversified the choice of students&rsquo; stress coping strategies. The behavior of the students from Kaliningrad and Poland was similar. The Belarusian students used active coping strategies less often, while an avoidance-focused style, and denial were more frequent. The neglect of restrictive anti-pandemic measures by the Belarusian students was manifested by a higher incidence of disease and minimal use of vaccinations

Abstract 1128: Identification of arginine methyltransferase PRMT5 as a novel therapeutic target in T-cell acute lymphoblastic leukemia

Abstract Advances in risk-adapted cytotoxic chemotherapy, hematopoietic stem cell transplantation and supportive care have contributed to significant improvements in the survival of patients with acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) over the past few decades. However, despite such progress, a significant percentage of both adult and pediatric leukemia patients become refractory to therapy or relapse and eventually die of disease. Hence, there remains an urgent need for the development of effective and targeted therapies for acute leukemia. Recent genetic profiling of solid and hematologic malignancies has identified epigenetic factors as a critical group of genes recurrently mutated in cancer. Additionally, epigenetic dysregulation has been shown to play an important role in the development, progression and maintenance of leukemia. Therefore, pharmacological inhibition of epigenetic factors represents a potential avenue for the development of novel epigenetic-targeted therapies. In order to identify epigenetic vulnerabilities in leukemia, we developed an epigenetic-focused shRNA screen to search for novel therapeutic targets in human leukemia cell lines both in vitro and in vivo. Specifically, T- and B-ALL cell lines were transduced with a library of shRNAs targeting 449 genes including epigenetic readers, writers and erasers and other chromatin-related factors. Selected cells were subsequently cultured in vitro and concurrently injected into mice. Engraftment of inoculated cells and disease progression were monitored through bioluminescence imaging. Amongst the universe of epigenetic regulatory proteins, the arginine methyl transferase, PRMT5, emerged as the most significantly depleted factor in both in vitro and in vivo screenings. Chemical inhibition of PRMT5 enzymatic activity effectively reduced protein symmetric dimethyl arginine methylation, altered splicing, inhibited cell growth and promoted apoptosis of both ALL and AML cell lines in vitro. In addition, inhibition of PRMT5 in vivo using patient-derived xenograft (PDX) T-ALL mouse models demonstrated diminished tumor growth and prolonged survival. Notably, quantification of peripheral blood cell numbers showed that pharmacologic PRMT5 inhibition was well tolerated and did not affect normal hematopoiesis in mice suggesting that a therapeutic window exists for anticancer drugs targeting PRMT5 in acute leukemia. Overall, our data indicates that pre-mRNA processing and in particular RNA splicing modulation may represent novel therapeutic targets in leukemia. Note: This abstract was not presented at the meeting. Citation Format: Yunyue Wang, Hui Huang, Daniel Diolaiti, Marta Sanchez Martin, Beata Modzelewski, Lianna J. Marks, Allison R. Rainey, Ervin S. Gaviria, Maria L. Sulis, Filemon S. Dela Cruz, Adolfo A. Ferrando, Andrew L. Kung. Identification of arginine methyltransferase PRMT5 as a novel therapeutic target in T-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1128. doi:10.1158/1538-7445.AM2017-1128</jats:p

A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma

Abstract Background Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities. Methods We utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient’s tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options. Results WES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK. Conclusions This clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis

Additional file 1: Figure S1. of A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma

Activation of mTOR pathway in patient tumor sample. Figure S2 A. Levels of in vitro translated MAX, MAXR60Q, C-MYC, and MXD1 in samples used for EMSA. B Modeling BRAF kinase domain complexed with ATP and Mg2+. Figure S3. Validation of PDX tumor model by Sanger sequencing. Figure S4. Tumor response to selumetinib. (PDF 7254 kb