Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results.

Purpose: Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.

Coexistence of lymphoproliferative and myeloproliferative neoplasms with simultaneous CALR and JAK2 V617F mutations.

Background: Hematopoietic malignancies are a group of blood cell disorders characterized by abnormal hematopoietic proliferation.

Objective: The identification of specific clinicopathologic characteristics and tumor-related gene status provides critical information on potential therapeutic targets.

Methods: The specimens were tested with immunohistochemistry, flow cytometry, RT-PCR and fragment analysis.

Gain of copy number and amplification of the RET gene in lung cancer.

RET rearrangement represents a unique molecular subset of lung cancer. The identification of specific clinicopathologic characteristics and RET gene status would provide critical information on targeted therapeutics. In this study, we investigated the patterns of RET gene in a series of lung carcinomas.

Diagnosis of paroxysmal nocturnal hemoglobinuria in peripheral blood and bone marrow with six-color flow cytometry.

Aim: Identification of paroxysmal nocturnal hemoglobinuria (PNH) by detecting a glycophosphatidylinositol-anchored defect by flow cytometry is presently the standard method of choice for diagnosing PNH. However, the selection of suitable markers will be critical and significantly affect the determination and quantification of PNH clones in various cell lineages.

Materials & Methods: In this study, we investigated the performance of various immunophenotypic markers including CD59, GPHA (a clustered antigen, CD235a), CD33, CD15 and fluorescent aerolysin (FLAER) combined with CD16, CD24 and CD14 in a PNH panel using six-color flow cytometry.

Risk stratification of plasma cell neoplasm: insights from plasma cell-specific cytoplasmic immunoglobulin fluorescence in situ hybridization (cIg FISH) vs. conventional FISH.

Unlabelled: We directly compared the results of routine fluorescence in situ hybridization (FISH) and plasma cell-specific cytoplasmic immunoglobulin (cIg) FISH from 75 paired samples for myeloma risk stratification. CIg FISH improves test specificity and sensitivity and tends to eliminate borderline results. It proves that most plasma cells (PCs) consistently carry the abnormality in myelomas with an IGH translocation, whereas routine FISH detects these cells only at variably low levels.

CD71 is selectively and ubiquitously expressed at high levels in erythroid precursors of all maturation stages: a comparative immunochemical study with glycophorin A and hemoglobin A.

Histology assessment of erythroid precursors in bone marrow biopsies can be challenging under pathologic conditions and often requires ancillary studies. CD71 (transferring receptor-1) is known to be expressed in the earliest erythroid precursors, and has been useful for flow cytometry. However, CD71 is also regarded as a proliferation marker, and its lineage specificity has not been systemically investigated by immunohistochemistry in detail.

pRb-mediated control of epithelial cell proliferation and Indian hedgehog expression in mouse intestinal development.

Background: Self-renewal of the epithelium of the small intestine is a highly regulated process involving cell proliferation and differentiation of stem cells or progenitor cells located at the bottom of the crypt, ending ultimately with extrusion of the terminally differentiated cells at the tip of villus.

Results: Here, we utilized the Cre/loxP system to investigate the function of the retinoblastoma protein, pRb in intestinal epithelium. pRb null mice displayed a profoundly altered development of the intestine with increased proliferation and abnormal expression of differentiation markers.

Cellular senescence requires CDK5 repression of Rac1 activity.

Cellular senescence is a tumor-suppressive process characterized by an irreversible cell cycle exit, a unique morphology, and expression of senescence-associated beta-galactosidase (SA-beta-Gal). We report here a role for CDK5 in induction of senescent cytoskeletal changes. CDK5 activation is upregulated in senescing cells.

ERM proteins and Cdk5 in cellular senescence.

Cellular senescence is a tumor-suppressive process instigated by proliferation in the absence of telomere replication, by cellular stresses such as oncogene activation, or by activation of the retinoblastoma tumor suppressor protein, pRb. This process is characterized by an irreversible cell cycle exit, a unique morphology, and expression of senescence-associated-beta-galactosidase (SA-beta-gal). Despite the potential biological importance of cellular senescence, little is known of the mechanisms leading to the senescent phenotype.

pRb inactivation in senescent cells leads to an E2F-dependent apoptosis requiring p73.

Senescent cells in which pRb is inactivated undergo apoptosis on attempted reinitiation of DNA synthesis. To further explore the cell death resulting from loss of pRb function in senescent cells, we employed a temperature-sensitive pRb mutant protein (tspRb). We found that tspRb inactivation results in rapid E2F reactivation and subsequent S-phase reentry associated with the up-regulation of E2F target gene expression and cyclin E-dependent kinase activity.

The role of transforming growth factor alpha in determining growth factor independence.

Growth factor independence is a hallmark of malignancy that is attributed to the development of autocrine growth factor loops in cancer cells. However, growth factor-dependent normal cells also exhibit autocrine activity, thus raising the issue of how endogenously produced activity in cancer cells differs in a manner that leads to growth factor independence. We have examined this issue by comparing growth factor-independent HCT116 human colon carcinoma cells with a growth factor-dependent subcompartment of malignant cells designated HCT116b that was isolated from the same patient tumor.

Increased ezrin expression and activation by CDK5 coincident with acquisition of the senescent phenotype.

Passage of normal cells in culture leads to senescence, an irreversible cell cycle exit characterized by biochemical changes and a distinctive morphology. Cellular stresses, including oncogene activation, can also lead to senescence. Consistent with an anti-oncogenic role for this process, the tumor suppressor pRb plays a critical role in senescence.

Role of the retinoblastoma protein in differentiation and senescence.

The retinoblastoma protein pRb is functionally inactivated in most human cancers. Numerous studies in cell culture and animal models suggest that pRb has a unique ability to encourage and enforce permanent cell cycle withdrawal, consistent with its role as a tumor suppressor protein. This cell cycle withdrawal has a generic component involving repression of transcription of genes required for proliferation.