Molecular mechanisms and pathogenetic role of BCL6 deregulation in diffuse large B-cell lymphomas — clinical and therapeutic implications

Deregulacja onkogenu BCL6 jest najczęstszym zaburzeniem molekularnym w chłoniaku rozlanymz dużych komórek B (DLBCL) u dorosłych. Gen BCL6 po raz pierwszy sklonowanoz translokacji chromosomalnych dotyczących 3q27. Gen ten koduje białko należące do rodzinyrepresorów transkrypcyjnych charakteryzujących się obecnością domeny BTB/POZ oraz palcówcynkowych. Dimeryzacja BCL6 powoduje rekrutację korepresorów, które odpowiadają zazróżnicowane biologiczne funkcje tego białka. Ekspresja BCL6 w limfocytach B jest niezbędnado rozpoczęcia reakcji germinalnej, w trakcie której komórki B intensywnie proliferująi wskutek procesów edycji sekwencji genów immunoglobulinowych zwiększają powinowactwoprzeciwciał do antygenu. W obrębie centrum germinalnego BCL6 kontroluje ekspresję genów,których represja zwiększa tolerancję na fizjologiczne uszkodzenia DNA wynikające ze specyfikireakcji germinalnej, reguluje progresję cyklu komórkowego, aktywację limfocytów oraz ichróżnicowanie. Wyciszenie ekspresji BCL6 jest wymagane do zakończenia reakcji germinalneji dalszego różnicowania limfocytów w komórki pamięci lub plazmocyty. Konstytutywna ekspresjaBCL6 wskutek zaburzeń strukturalnych lub mechanizmów czynnościowych uniemożliwiaróżnicowanie limfocytów, sprzyja akumulacji dodatkowych zaburzeń genetycznych i indukujepowstanie DLBCL. Z tego względu inhibicja aktywności BCL6 może stanowić racjonalnycel terapeutyczny w chłoniakach z deregulacją tego onkogenu i czynnościowo zależnych od jegoekspresji. Poznanie molekularnych zależności między strukturą i funkcją białka BCL6 pozwoliłona podjęcie prób projektowania molekuł, które mogłyby specyficznie rozrywać interakcjeBCL6 z określonymi zestawami korepresorów i swoiście blokować jego określone funkcje.Niniejszy artykuł stanowi przegląd doniesień dotyczących roli BCL6 w genezie DLBCL orazobecnego stanu zaawansowania badań dotyczących celowanych inhibitorów BCL6.BCL6 is the most frequently deregulated oncogene in diffuse large B-cell lymphoma (DLBCL),the most common lymphoma in adults. BCL6 gene was first cloned from recurringchromosomal translocations involving 3q27. BCL6 encodes a member of the BTB/POZ zincfinger family of transcriptional repressors. Upon dimerization, BCL6 recruits distinct sets ofcorepressors that mediate its biological activity. BCL6 expression in B-cells is required forformation of germinal centers (GC). Within the GC, BCL6 controls the expression of multiplegenes that increase the tolerance to the physiological DNA breaks required for immunoglobulinaffinity maturation, regulate cell cycle progression, B-cell activation and differentiation.Downregulation of BCL6 is required for B-cells to undergo further differentiation to memorycells or plasma cells. Constitutive expression of BCL6 due to structural or functionalabnormalities in humans and mice inhibits B-cell differentiation and fosters acquisition ofadditional lesions, leading to DLBCL. For these reasons, BCL6 represents a rationaltherapeutic target in DLBCL with deregulated expression of this oncogene and reliant on itscontinuous activity. Dissection of molecular structure-function relationships of the BCL6protein allowed to design molecules specifically targeting this transcription factor and blockingits function. Herein, we review recent advances in understanding the role of BCL6 inlymphomagenesis and approaches to its therapeutic targeting

Deregulation of MYC transcription factor in lymphoid tumors — molecular, pathogenetic, clinical and therapeutic implications

Czynnik transkrypcyjny MYC jest jednym z najczęściej deregulowanych onkogenów w ludzkichnowotworach. Gen MYC koduje białko należące do rodziny czynników transkrypcyjnychzawierających motyw suwaka leucynowego, kontrolujące szeroki zakres genów odpowiedzialnychza przyspieszoną proliferację, metabolizm komórkowy, wzrost, angiogenezę, zdolność dotworzenia przerzutów, niestabilność genetyczną, potencjał odtwórczy komórek macierzystychoraz zredukowaną zdolność różnicowania. W mysich modelach rozwinięcie pełnego fenotypunowotworów zainicjowanych przez MYC wymaga dodatkowych zmian, takich jak: mutacjeścieżki p53, mutacje TCF3, aktywność PI3K oraz zaburzenia białek z rodziny BCL2.W ludzkich nowotworach komórek B rearanżacje MYC obejmujące region 8q24 oraz genyimmunoglobulinowe są cechą charakterystyczną chłoniaka Burkitta, ale występują równieżw innych nowotworach. W chłoniaku rozlanym z dużych komórek B MYC jest trzecim, poBCL6 i BCL2, najczęściej deregulowanym onkogenem. Proste rearanżacje MYC/IGH są rzadkospotykane w tych nowotworach i częściej dotyczą genów łańcuchów lekkich lub genównieimmunoglobulinowych oraz towarzyszą złożonym kariotypom. Najczęstszą cytogenetycznąnieprawidłowością towarzyszącą MYC jest t(14;18) dotycząca BCL2 lub rzadziej rearanżacjeBCL6. Takie chłoniaki double/triple-hit, zawierające rearanżacje BCL2 i/lub BCL6 wrazz nieprawidłowościami MYC, często mają nietypowe cechy morfologiczne i immunofenotypoweoraz charakteryzują się agresywnym przebiegiem. Biorąc pod uwagę szeroki zakres funkcjiMYC, inhibicja jego aktywności może być racjonalną strategią terapeutyczną w leczeniu chłoniakówwykazujących nadekspresję tego onkogenu. W poniższym artykule dokonano przeglądupatogenetycznych mechanizmów związanych z deregulacją MYC w ludzkich nowotworachz komórek B oraz potencjału terapeutycznego inhibitorów tego czynnika transkrypcyjnego.MYC transcription factor is one of the most frequently deregulated oncogenes in humanmalignancies. It encodes a leucine zipper transcription factor that controls a broad spectrum ofcellular genes responsible for enhanced proliferation, cellular metabolism, growth, vasculogenesis,metastasis, genomic instability, stem cell self-renewal and reduced differentiation. Inmouse models, full-blown phenotype of MYC-driven tumors requires cooperation with otherlesions, including p53 pathway mutations, TCF3 mutations, PI3K activity and BCL2 familyabnormalities. In human B-cell tumors, MYC rearrangements involving 8q24 region andimmunoglobulin genes are hallmark of Burkitt lymphoma, but also occur in other lymphoidmalignancies. In diffuse large B-cell lymphoma, MYC is the third, after BCL6 and BCL2,most commonly deregulated oncogene. Simple MYC/IGH rearrangements in these tumors areuncommon and more frequently involve light chain or non-IG partners and exist in the settingof complex karyotypes. The most common cytogenetic abnormality accompanying MYC ist(14;18) involving BCL2 and less frequently BCL6. Such “double/triple hit” B-cell tumorsharboring BCL2 and/or BCL6 rearrangements concurrent with MYC lesions frequently exhibitatypical morphologic and/or immunophenotypic features and particularly aggressive clinicalbehavior. Given the broad range of MYC functions, inhibition of MYC activity might bea rational therapeutic strategy in lymphoid tumors expressing this oncogene. Several approachesfor pharmaceutical intervention have been suggested. Herein, we review the molecularpathogenetic mechanisms associated with MYC deregulation in human B-cell tumors and itsimplications for such targeted therapies

New CRISPR Mutagenesis Strategies Reveal Variation in Repair Mechanisms among Fungi

We have created new vectors for clustered regularly interspaced short palindromic repeat (CRISPR) mutagenesis in Candida albicans, Saccharomyces cerevisiae, Candida glabrata, and Naumovozyma castellii These new vectors permit a comparison of the requirements for CRISPR mutagenesis in each of these species and reveal different dependencies for repair of the Cas9 double-stranded break. Both C. albicans and S. cerevisiae rely heavily on homology-directed repair, whereas C. glabrata and N. castellii use both homology-directed and nonhomologous end-joining pathways. The high efficiency of these vectors permits the creation of unmarked deletions in each of these species and the recycling of the dominant selection marker for serial mutagenesis in prototrophs. A further refinement, represented by the "Unified" Solo vectors, incorporates Cas9, guide RNA, and repair template into a single vector, thus enabling the creation of vector libraries for pooled screens. To facilitate the design of such libraries, we have identified guide sequences for each of these species with updated guide selection algorithms.IMPORTANCE CRISPR-mediated genome engineering technologies have revolutionized genetic studies in a wide range of organisms. Here we describe new vectors and guide sequences for CRISPR mutagenesis in the important human fungal pathogens C. albicans and C. glabrata, as well as in the related yeasts S. cerevisiae and N. castellii The design of these vectors enables efficient serial mutagenesis in each of these species by leaving few, if any, exogenous sequences in the genome. In addition, we describe strategies for the creation of unmarked deletions in each of these species and vector designs that permit the creation of vector libraries for pooled screens. These tools and strategies promise to advance genetic engineering of these medically and industrially important species.National Institutes of Health (U.S.) (Grant GM035010)National Institutes of Health (U.S.) (Grant GM118135)National Institutes of Health (U.S.) (Grant R15AI130950

Ecological Analysis of Heat Pumps in Poland in Terms of Carbon Dioxide Emissions

The purpose of this work is a comparison of indirect carbon dioxide emissions between the different heat pump types that operate in Polish climate conditions. This analysis embraces an air–water heat pump (ASHP), ground–water heat pump (GSHP), water–water heat pump (WSHP), and a WSHP with a separating heat exchanger (SHE) in the selected towns, one in each climatic zone in the country. The study starts from a computation of heat demand and electrical energy consumption in every hour of the heating season using temperature values taken from a typical meteorological year (TMY). Then, seasonal coefficient of performance (SCOP) values are determined, which enables an assessment of which kind of heat pump meets the European Union requirements in every location. Eventually, indirect CO2 emissions that are caused by electrical energy production are estimated for every heat pump in each location

An Ecological Profitability Assessment of the Heat Pumps in Poland

Indirect greenhouse gases emissions due to electricity production for powering heat pumps are compared in all Polish climatic zones. The different meteorological conditions are defined by the typical meteorological year. The comparison is made for air-to-water, brine-to-water and water-to-water devices. It starts from determining electrical energy consumption and coefficient of performance value in every hour of a heating season. The determination algorithm takes into consideration a buffer tank or separating heat exchanger when one is required. Subsequently the emissions estimations are done for the present Polish energy mix and assumed one in “Energy policy of Poland until 2040”

An Environmental Assessment of Heat Pumps in Poland

Greenhouse gas emissions are regarded as the cause of the rise in mean Earth temperature, the further increase of which may cause dramatic irreversible global changes. Their levels in Poland are some of the highest in the world. In this study, to evaluate the “Energy policy of Poland until 2040”, greenhouse gas and particulate matter emissions were compared in all Polish climatic zones using a typical meteorological year. A comparison was made between air-to-water, brine-to-water, and water-to-water devices. The electrical energy consumption and coefficient of performance were determined hourly in the heating season. The determining algorithm took a buffer tank or separating heat exchanger into consideration, when they were required, and electricity transmission efficiency. Subsequently the emissions were estimated for the present Polish energy mix and a mix proposed in the “Energy policy of Poland until 2040”. After implementing this policy all heat pumps will be energetically viable devices. However, only in one location will water-to-water heat pumps cause less emissions than a condensing gas boiler. In other cases, condensing gas boilers will be significantly less emissive devices. Therefore, this policy is insufficient for reducing emissions. Hence, it is necessary to replace almost all coal-fired power plants with natural gas-fired gas turbines in a transitional period

An Environmental Assessment of Heat Pumps in Poland

Greenhouse gas emissions are regarded as the cause of the rise in mean Earth temperature, the further increase of which may cause dramatic irreversible global changes. Their levels in Poland are some of the highest in the world. In this study, to evaluate the “Energy policy of Poland until 2040”, greenhouse gas and particulate matter emissions were compared in all Polish climatic zones using a typical meteorological year. A comparison was made between air-to-water, brine-to-water, and water-to-water devices. The electrical energy consumption and coefficient of performance were determined hourly in the heating season. The determining algorithm took a buffer tank or separating heat exchanger into consideration, when they were required, and electricity transmission efficiency. Subsequently the emissions were estimated for the present Polish energy mix and a mix proposed in the “Energy policy of Poland until 2040”. After implementing this policy all heat pumps will be energetically viable devices. However, only in one location will water-to-water heat pumps cause less emissions than a condensing gas boiler. In other cases, condensing gas boilers will be significantly less emissive devices. Therefore, this policy is insufficient for reducing emissions. Hence, it is necessary to replace almost all coal-fired power plants with natural gas-fired gas turbines in a transitional period

Energetic and Ecologic Heat Pumps Evaluation in Poland

The purpose of the work is a comparison of indirect carbon dioxide emissions between the different heat pump types that operate in Polish climate conditions. The analysis embraces air-to-water heat pump, ground-to-water heat pump, water-to-water heat pump and water-to-water heat pump with separating heat exchanger in the selected towns one in each climatic zone in the country. The study starts from determining seasonal coefficient of performance in each location using heating degree days to estimate seasonal heat demand. Seasonal coefficient of performance values enable an assessment which kind of heat pump meets the European Union requirements in every location. Eventually, indirect CO2 emissions that is caused by electrical energy production, are estimated for every heat pump in each location. Ground-to-water heat pump and water-to-water heat pump satisfy these requirements in each climatic zone in Poland. Air-to-water heat pump would be an energetic and ecological viable on a condition that substantial changes were done in Polish electrical energy mix

Carbon Dioxide Emissions from a Ground Heat Pump for a Detached House

Inasmuch as the European Union promotes only energetically viable heat pumps in a given location, the aim of the work is an assessment of whether a ground-to-water heat pump (ground source heat pump: GSHP) can be considered as an ecological heat generator in Polish climatic conditions and those of the energy market. Here, as an estimator, the net seasonal coefficient of performance (SCOPnet) was selected. Estimation was done using 10-year temperature measurements. It was found that in heating mode SCOPnet value equaled 4.83, satisfying European Commission guidelines. According to the guidelines, the minimal SCOPnet value in Polish energy market conditions should exceed 3.5. CO2 emissions from the GSHP represented two-thirds of CO2 emissions of an air-to-water heat pump (air source heat pump: ASHP) in the same building. The ground heat pump thus meets the ecological heat generator conditions set by the European Commission

Long-Term Assessment of Periodontal Tissues after Corticotomy-Assisted Orthodontic Arch Expansion

Objectives: The aim of the study was the long-term assessment of the condition of periodontal tissues after corticotomy-assisted orthodontic expansion in patients with transverse maxillary deficiency. Materials and Methods: The study included a group of 18 adults (9 women, 9 men) aged between 24 and 40 years who were at least 5 years post treatment. The following parameters were assessed: the full mouth plaque index (FMPI), full mouth bleeding on probing (FMBOP), probing depth (PD), clinical attachment level (CAL), gingival recession height (GR), recession width (RW), papilla height (PH), papilla width (PW), bone sounding (BS), phenotype, and KT. Results: During examination performed at least 5 years after the completion of orthodontic treatment, the values of PD and CAL were found to be considerably decreased compared to the examination one year post treatment (PD: −0.23; 95% Cl: −0.29, −0.16) (CAL: −0.04; 95% Cl: −0.17, 0.10). The other parameters—FMPI, FMBOP, GR, RW, PH, PW, BS, phenotype, and KT—did not change significantly. Conclusions: Corticotomy-assisted orthodontic arch expansion does not have a negative effect on the periodontium in long-term observations. Clinical Relevance: Orthodontic arch expansion can lead to bone dehiscence and gingival recession. Long-term observations revealed that corticotomy-assisted orthodontic expansion of the upper arch is not followed by negative changes in periodontal status