Rhabdomyolysis and Acute Renal Dysfunction as Initial Manifestations of Monoclonal Gammopathy of Renal Significance.

Monoclonal gammopathy of renal significance (MGRS) is a rare heterogeneous group of kidney disorders that encompasses all disorders caused by deposition of monoclonal protein (M-protein) and its light or heavy chain fragments secreted by pre-malignant or non-malignant B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma (MM) or other B-cell malignancies. MGRS can manifest as glomerular diseases, tubulopathies, or vascular involvement with varying clinical presentations, making the diagnosis of MGRS challenging. In patients with high clinical suspicion based on preliminary blood and urine studies, the evaluation of MGRS begins with a renal biopsy followed by monoclonal studies and cytogenetic analysis. There is no standard treatment protocol for MGRS, and the current consensus suggests a clone-directed approach. If not identified and treated early, MGRS often results in poor outcomes and can lead to extrarenal manifestations, such as cardiogenic shock. Herein, we present a case involving a 43-year-old male with a rare presentation of rhabdomyolysis, rapidly progressing renal dysfunction, and cardiac dysfunction. A bone marrow biopsy did not meet the diagnostic criteria for MM or other B-cell malignancies, while a renal biopsy revealed Kappa light chain cast nephropathy, which led to the final diagnosis of MGRS.

Early transformation event from follicular lymphoma: our experience of four cases.

Follicular lymphoma (FL) is a mature B-cell lymphoma that can transform into a more aggressive disease such as diffuse large B-cell lymphoma, Burkitt lymphoma, or precursor B-lymphoblastic leukaemia/lymphoma. The process of transformation of FL occurs by the acquisition of additional genetic alterations, e.g. c-MYC rearrangement, TP53, and cyclin D1 inactivation. Herein, we describe four such cases of FL that transformed into more aggressive B-cell non-Hodgkin lymphomas within six months of their initial diagnosis. Subsequent testing of c-myc, P53 and cyclin D1 by immunohistochemistry and fluorescence in situ hybridization was done to further analyse their role in the process of transformation.

Treatment-related peripheral small cell lung carcinoma in a Hodgkin lymphoma survivor.

Hodgkin lymphoma (HL) survivors have an increased risk of developing subsequent treatment-related primary malignancies. In the last few decades, advances in knowledge, radiotherapy, chemotherapy and autologous stem cell transplantation have led to the transformation of lethal malignancy into highly curable malignancy, thereby improving outcomes. With prolonged survival, the risk of developing subsequent treatment-related late adverse effects, such as malignancies, steadily increases over time. Herein, we present the first case of a treatment-related second primary stage IV peripheral small cell lung carcinoma in a female HL survivor who was also diagnosed with right breast cancer 13 years after HL treatment and 1 year before her lung cancer diagnosis.

Clear cell renal cell carcinoma with stage IV cavoatrial tumour thrombus extension and rapid metastatic reoccurrence postsurgical treatment with review of current treatment strategies.

Renal cell carcinoma (RCC) is the most aggressive urological malignancy, with a high recurrence rate. Despite the rapid evolution of the treatment of RCC from non-specific cytotoxic therapies to specific novel combination therapies, the general prognosis for advanced RCC remains poor because patients' responses to these therapies vary. Herein, we present the case of a male in early forties who was diagnosed with a right lower pole renal mass with a level IV tumour thrombus, which was later confirmed as stage IIIc clear cell RCC. About 19 months after radical nephrectomy (curative surgery), the patient was diagnosed with a biopsy-proven metastatic disease, which was not responsive to first-line treatment owing to insufficient data on the best treatment regimen. Herein, we also present a literature review on the pathological impact of genomic alterations in tumour suppressors and highlight emerging paradigm shifts in the treatment of RCC.

TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization.

While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.

Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia.

Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.

Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways.

Many functions of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) have been defined, but relatively little is known about the biology of an alternative mTOR complex, mTORC2. We showed that conditional deletion of rictor, an essential subunit of mTORC2, impaired differentiation into T helper 1 (Th1) and Th2 cells without diversion into FoxP3(+) status or substantial effect on Th17 cell differentiation. mTORC2 promoted phosphorylation of protein kinase B (PKB, or Akt) and PKC, Akt activity, and nuclear NF-kappaB transcription factors in response to T cell activation. Complementation with active Akt restored only T-bet transcription factor expression and Th1 cell differentiation, whereas activated PKC-theta reverted only GATA3 transcription factor and the Th2 cell defect of mTORC2 mutant cells. Collectively, the data uncover vital mTOR-PKC and mTOR-Akt connections in T cell differentiation and reveal distinct pathways by which mTORC2 regulates development of Th1 and Th2 cell subsets.

PARP-14, a member of the B aggressive lymphoma family, transduces survival signals in primary B cells.

Poly(ADP-ribos)ylation is one of the longest-known but most enigmatic posttranslational modifications transducing specific signals. The enzyme responsible for the majority of poly(ADP-ribose) polymerization in cells, PARP-1, promotes DNA repair but also mediates a caspase-independent form of apoptosis in response to stressors such as irradiation. However, the biologic function of most other PARPs is not known. Macro-PARPs constitute one branch of the large family of PARP-like proteins also designated as B aggressive lymphoma proteins (BAL1, 2a/2b, 3, or PARP-9, PARP-14, and PARP-15). To elucidate biologic role(s) of a BAL-family macro-PARP, we analyzed mice deficient in PARP-14, a binding partner of the IL-4-induced transcription factor Stat6. We show here that PARP-14 plays a fundamental role mediating protection against apoptosis in IL-4-treated B cells, including that after DNA damage, and mediates IL-4 effects on the levels of gene products that regulate cell survival, proliferation, and lymphomagenesis. Collectively, the results establish that PARP-14 mediates regulation of gene expression and lymphocyte physiology by IL-4 and has a function distinct from PARP-1. Furthermore, the findings suggest mechanisms by which BAL-family proteins might influence pathologic processes involving B lymphocytes.

Flexibility accompanies commitment of memory CD4 lymphocytes derived from IL-4 locus-activated precursors.

Differentiation of T helper (Th) subset 2 effector lymphocytes is thought to foreclose on IFN-gamma gene expression. Using an IL-4 locus modified to detect transcriptional induction of this effector cytokine gene in developing Th2 cells, we show here that these cells contributed effectively to a long-term memory population. A memory CD4 subset formed efficiently from an activated population after transcriptional induction of the IL-4 locus and differentiation into an IL-4-producing subset with Th2 characteristics. Memory lymphocytes derived from Th2 cells with IL-4 locus activation remained committed to transcriptional competence of Th2 cytokine genes when reactivated and cultured under strong Th1-polarizing conditions. This commitment to transcriptional competence at Th2 cytokine gene loci upon recall activation indicates that linear differentiation is a substantial component of type 2 memory. Strikingly, however, descendants of the Th2 population could turn on IFN-gamma expression when reactivated after a quiescent period, revealing an unexpected flexibility allowing activation of the forbidden IFN-gamma gene after reactivation and growth.

Differential requirement of signal transducer and activator of transcription-4 (Stat4) and Stat6 in a thyrotropin receptor-289-adenovirus-induced model of Graves' hyperthyroidism.

T helper type 1 (Th1) and Th2 cells have critical roles in the development of cell-mediated and humoral immune responses, respectively. This division of function predicts that Th1 cells mediate inflammatory diseases and Th2 cells promote antibody (Ab)-mediated autoimmunity. Our previous studies using HEK-293 cells expressing the extracellular domain of the TSH receptor (TSHR) showed that Stat4-/- mice, which lack Th1 cells, are susceptible, whereas Stat6-/- mice, which lack Th2 cells, are resistant to the induction of Graves' hyperthyroidism. To investigate the role of Stat4 and Stat6 genes in other murine models of hyperthyroidism, we injected wild-type BALB/c, Stat4-/-, and Stat6-/- mice with an adenovirus expressing amino acid residues 1-289 of TSHR (TSHR-289-ad or 289-ad). The viral system induces a much stronger immune response with much more rapid onset of disease. Our results showed that 56% of wild-type, 75% of Stat4-/-, and 39% of Stat6-/- mice developed hyperthyroidism. Hyperthyroid mice exhibited thyroid stimulatory Abs. The Stat4-/- mice developed a higher incidence and greater severity of hyperthyroidism compared with wild-type and Stat6-/- mice. BALB/c and Stat4-/- mice showed significantly higher TSHR Abs of the IgG1 subclass and IL-4 compared with Stat6-/- mice. In contrast, Stat6-/- mice had predominantly the IgG2a subclass of TSHR Ab and produced significantly higher amounts of IFN-gamma than BALB/c and Stat4-/- mice. All hyperthyroid mice showed enlarged thyroid glands with hyperactivity. These results suggest that in the TSHR-289-ad model, the Th2 cells are more efficient in mediating disease, but in the absence of Th2 cells, Th1 cells may still initiate a reduced incidence of Graves' hyperthyroidism.