Primary gastric T cell lymphoma mimicking marginal zone B cell lymphoma of mucosa-associated lymphoid tissue

Primary gastric T cell lymphoma is rare and mostly of large cell type. In this paper, we present a case of gastric T cell lymphoma morphologically similar to the gastric marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT). Morphologically, the cells are small with abundant clear cytoplasm. Lymphoepithelial lesions are readily identified with diffuse destruction of gastric glands. Immunohistochemically, the neoplastic cells are CD3+/CD4+/CD8−/Granzyme B−. Molecular studies revealed monoclonal T cell receptor γ gene rearrangement. Clinically, the patient responded initially to four cycles of R-CHOP, but then progressed. Because peripheral T cell lymphoma is usually associated with a poor prognosis, whereas marginal zone B cell lymphoma is an indolent lymphoproliferative disorder, this morphologic mimicry should be recognized and completely investigated when atypical small lymphoid infiltrates with lymphoepithelial lesions are encountered in the stomach

A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. © 2018 AAC

Factors in perioperative care that determine blood loss in liver surgery

AbstractObjectivesExcessive blood loss during liver surgery contributes to postoperative morbidity and mortality and the minimizing of blood loss improves outcomes. This study examines pre- and intraoperative factors contributing to blood loss and identifies areas for improvement.MethodsAll patients who underwent elective hepatic resection between June 2007 and June 2009 were identified. Detailed information on the pre- and perioperative clinical course was analysed. Univariate and multivariate analyses were used to identify factors associated with intraoperative blood loss.ResultsA total of 175 patients were studied, of whom 95 (54%) underwent resection of three or more segments. Median blood loss was 782ml. Greater blood loss occurred during major resections and prolonged surgery and was associated with an increase in postoperative complications (P= 0.026). Peak central venous pressure (CVP) of >10cm H2O was associated with increased blood loss (P= 0.01). Although no differences in case mix were identified, blood loss varied significantly among anaesthetists, as did intraoperative volumes of i.v. fluids and transfusion practices.ConclusionsThis study confirms a relationship between CVP and blood loss in hepatic resection. Intraoperative CVP values were higher than those described in other studies. There was variation in the intraoperative management of patients. Collaboration between surgical and anaesthesia teams is required to minimize blood loss and the standardization of intraoperative anaesthesia practice may improve outcomes following liver surgery

Successful Treatment of Intracranial Hemorrhage with Recombinant Activated Factor VII in a Patient with Newly Diagnosed Acute Myeloid Leukemia: A Case Report and Review of the Literature

Intracranial hemorrhage (ICH) is a common complication in acute myeloid leukemia (AML) patients with an incidence rate of 6.3% [1]. Bleeding disorders related to disseminated intravascular coagulation (DIC) are common complications in AML cases [2]. Recombinant activated Factor VII (rFVIIa [NovoSeven®]) is approved for the treatment of bleeding complications with FVIII or FIX inhibitors in patients with congenital FVII deficiency. Use of rFVIIa for the treatment of acute hemorrhage in patients without hemophilia has been successful [3,4]. Herein, we describe the successful use of rFVIIa in a patient with acute ICH in the setting of newly diagnosed AML

Rotatable Zero Knowledge Sets: Post Compromise Secure Auditable Dictionaries with application to Key Transparency

Key Transparency (KT) systems allow end-to-end encrypted service providers (messaging, calls, etc.) to maintain an auditable directory of their users’ public keys, producing proofs that all participants have a consistent view of those keys, and allowing each user to check updates to their own keys. KT has lately received a lot of attention, in particular its privacy preserving variants, which also ensure that users and auditors do not learn anything beyond what is necessary to use the service and keep the service provider accountable. Abstractly, the problem of building such systems reduces to constructing so-called append-only Zero-Knowledge Sets (aZKS). Unfortunately, existing aZKS (and KT) solutions do not allow to adequately restore the privacy guarantees after a server compromise, a form of Post-Compromise Security (PCS), while maintaining the auditability properties. In this work we address this concern through the formalization of an extension of aZKS called Rotatable ZKS (RZKS). In addition to providing PCS, our notion of RZKS has several other attractive features, such as a stronger (extractable) soundness notion, and the ability for a communication party with out-of-date data to efficiently “catch up” to the current epoch while ensuring that the server did not erase any of the past data. Of independent interest, we also introduce a new primitive called a Rotatable Verifiable Random Function (VRF), and show how to build RZKS in a modular fashion from a rotatable VRF, ordered accumulator, and append-only vector commitment schemes

Влияние магнитомеханического резонанса на амплитудно- и фазочастотные зависимости переменных составляющих эффекта Фарадея

В рамках модели продольных колебаний тонкого стержня из магнитооптического кристалла в условиях магнитомеханического резонанса показано, что вынужденные колебания могут создавать не только амплитудные, но и фазочастотные зависимости переменных составляющих эффекта Фарадея.У рамках моделі поздовжніх коливань тонкого стрижня із магнітооптичного кристала в умовах магнітомеханічного резонансу показано, що вимушені коливання можуть створювати не тільки амплітудні, але й фазочастотні залежності змінних складових ефекту Фарадея.In the framework of a model of longitudinal vibrations of a thin rod fabricated of the magneto-optical crystal under a magnetomechanical resonance, it is shown that the forced oscillations can create not only the amplitude but also phase-frequency dependences of the variable components of the Faraday effect

Negative Elongation Factor Controls Energy Homeostasis in Cardiomyocytes

SummaryNegative elongation factor (NELF) is known to enforce promoter-proximal pausing of RNA polymerase II (Pol II), a pervasive phenomenon observed across multicellular genomes. However, the physiological impact of NELF on tissue homeostasis remains unclear. Here, we show that whole-body conditional deletion of the B subunit of NELF (NELF-B) in adult mice results in cardiomyopathy and impaired response to cardiac stress. Tissue-specific knockout of NELF-B confirms its cell-autonomous function in cardiomyocytes. NELF directly supports transcription of those genes encoding rate-limiting enzymes in fatty acid oxidation (FAO) and the tricarboxylic acid (TCA) cycle. NELF also shares extensively transcriptional target genes with peroxisome proliferator-activated receptor α (PPARα), a master regulator of energy metabolism in the myocardium. Mechanistically, NELF helps stabilize the transcription initiation complex at the metabolism-related genes. Our findings strongly indicate that NELF is part of the PPARα-mediated transcription regulatory network that maintains metabolic homeostasis in cardiomyocytes

Developing independent investigators for clinical research relevant for Africa

Sustainable research capacity building requires training individuals at multiple levels within a supportive institutional infrastructure to develop a critical mass of independent researchers. At many African medical institutions, a PhD is important for academic promotion and is, therefore, an important focal area for capacity building programs. We examine the training at the Infectious Diseases Institute (IDI) as a model for in-country training based on systems capacity building and attention to the academic environment. PhD training in Africa should provide a strong research foundation for individuals to perform independent, original research and to mentor others. Training the next generation of researchers within excellent indigenous academic centers of excellence with strong institutional infrastructure will empower trainees to ask regionally relevant research questions that will benefit Africans

Loss of Effector Function of Human Cytolytic T Lymphocytes Is Accompanied by Major Alterations in N- and O-Glycosylation

Most human tumors are not eliminated by the immune system, and therapeutic vaccination shows poor results, a fact that can be explained at least partially by an immunosuppressive tumor microenvironment that is abundant in galectin-3. On cytolytic T lymphocyte (CTL) clones, maintained in culture by regular stimulation, recently activated CTLs present low effector functions. However, these functions are restored after a short treatment with LacNAc. The latter, which is in agreement with the glycoprotein-galectin lattice concept involving reduced motility, poses the question why galectin-3 ligands improve effector functions. We employed ultrasensitive MALDI-TOF-MS on resting and recently activated CTL clones combined with various glycosidase digestions and GC-MS linkage analyses. Our results showed that compared with the resting CTLs, the N-glycans of the recently activated CTLs consisted of (i) larger LacNAc oligomers of which a significant portion was longer than four-units and (ii) more multi-antennary structures. Interestingly, our results showed that the poly-LacNAc appeared to be equally distributed on all available N-glycan branches and not selectively enriched on a specific branch. The above structural alterations in the recently activated CTLs are expected to increase the galectin-3-LacNAc lattices and multivalent interactions and, therefore, reduce the motility of surface glycoproteins, such as the T-cell receptor. These findings suggest that the loss of effector functions on CTLs may be linked to reduced motility of surface glycoproteins. In addition, our results showed that recently activated CTLs had a reduced abundance of NeuAcα2,6-linked N-glycans and an increased abundance of disialylated core 1 and monosialylated core 2 O-glycan structures