Explore the vast range of titles available.

Treatment of B-cell non-Hodgkin's lymphoma has become more successful, largely owing to the availability of therapeutic monoclonal antibodies, which may avoid the toxic effects of chemotherapy, improve the outcomes when combined with chemotherapy, and provide options for patients with refractory disease. This article reviews the current uses of monoclonal antibodies in B-cell non-Hodgkin's lymphoma. Treatment of B-cell non-Hodgkin's lymphoma has become more successful, largely owing to the availability of therapeutic monoclonal antibodies. This article reviews the current uses of monoclonal antibodies in B-cell non-Hodgkin's lymphoma. Non-Hodgkin's lymphoma is the most common hematologic cancer in adults, with more than 66,000 incident cases anticipated in the United States in 2008. 1 Approximately 85% of non-Hodgkin's lymphomas in adults are of B cell origin. 2 Some B-cell non-Hodgkin's lymphomas are indolent, or slow-growing, yet incurable. In contrast, others are aggressive or very aggressive, and may be rapidly fatal, yet are often curable. There has been a revolution in the treatment of B-cell non-Hodgkin's lymphomas, owing largely to the availability of therapeutic monoclonal antibodies. The concept that antibodies might be effective for the treatment of cancers originated more than a century . . .

Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles. In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809. 55 patients were enrolled (median age 59 years, IQR 51–67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40–218). Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study. Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.

Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.

Gaucher disease (GD) is caused by a deficiency of glucocerebrosidase and the consequent lysosomal accumulation of unmetabolized glycolipid substrates. Enzyme-replacement therapy adequately manages the visceral manifestations of nonneuronopathic type-1 Gaucher patients, but not the brain disease in neuronopathic types 2 and 3 GD. Substrate reduction therapy through inhibition of glucosylceramide synthase (GCS) has also been shown to effectively treat the visceral disease. Here, we evaluated the efficacy of a novel small molecule inhibitor of GCS with central nervous system (CNS) access (Genz-682452) to treat the brain disease. Treatment of the conduritol β epoxide-induced mouse model of neuronopathic GD with Genz-682452 reduced the accumulation of liver and brain glycolipids (>70% and >20% respectively), extent of gliosis, and severity of ataxia. In the genetic 4L;C* mouse model, Genz-682452 reduced the levels of substrate in the brain by >40%, the extent of gliosis, and paresis. Importantly, Genz-682452-treated 4L;C* mice also exhibited an ~30% increase in lifespan. Together, these data indicate that an orally available antagonist of GCS that has CNS access is effective at attenuating several of the neuropathologic and behavioral manifestations associated with mouse models of neuronopathic GD. Therefore, Genz-682452 holds promise as a potential therapeutic approach for patients with type-3 GD.

Sympatric ocelots (Leopardus pardalis) and bobcats (Lynx rufus) in South Texas show substantial overlap in body size, food habits, and habitat use. Consequently, we explore whether temporal niche partitioning may explain ocelot and bobcat coexistence. We investigated the influence of sun angle, lunar illumination, and maximum diurnal temperature on temporal movement rates of sympatric ocelots (n = 8) and bobcats (n = 6) using a combination of high-frequency GPS locations and bi-axial accelerometer data. We demonstrated that accelerometer data could be used to predict movement rates, providing a nearly continuous measure of animal activity and supplementing GPS locations. Ocelots showed a strong nocturnal activity pattern with the highest movement rates at night whereas bobcats showed a crepuscular activity pattern with the highest movement rates occurring around sunrise and sunset. Although bobcat activity levels were lower during the day, bobcat diurnal activity was higher than ocelot diurnal activity. During warmer months, bobcats were more active on nights with high levels of lunar illumination. In contrast, ocelots showed the highest nocturnal activity levels during periods of low lunar illumination. Ocelots showed reduced diurnal activity on hotter days. Our results indicate that ocelot and bobcat coexistence in South Texas can be partially explained by temporal niche partitioning, although both felids showed periods of overlapping activity during nocturnal and crepuscular periods.

Globoid cell leukodystrophy (Krabbe disease) is a fatal neurodegenerative, demyelinating disease caused by dysfunctional activity of galactosylceramidase (GALC), leading to the accumulation of glycosphingolipids including psychosine. While oligodendrocytes have been extensively studied due to their high levels of GALC, the contribution of astrocytes to disease pathogenesis remains to be fully elucidated. In the current study, we generated induced pluripotent stem cells (iPSCs) from two donors with infantile onset Krabbe disease and differentiated them into cultures of astrocytes. Krabbe astrocytes recapitulated many key findings observed in humans and rodent models of the disease, including the accumulation of psychosine and elevated expression of the pro-inflammatory cytokine IL-6. Unexpectedly, Krabbe astrocytes had higher levels of glucosylceramide and ceramide, and displayed compensatory changes in genes encoding glycosphingolipid biosynthetic enzymes, suggesting a shunting away from the galactosylceramide and psychosine pathway. In co-culture, Krabbe astrocytes negatively impacted the survival of iPSC-derived human neurons while enhancing survival of iPSC-derived human microglia. Substrate reduction approaches targeting either glucosylceramide synthase or serine palmitoyltransferase to reduce the sphingolipids elevated in Krabbe astrocytes failed to rescue their detrimental impact on neuron survival. Our results suggest that astrocytes may contribute to the progression of Krabbe disease and warrant further exploration into their role as therapeutic targets.

Telemedicine is now common practice for many fields of medicine, but questions remain as to whether telemedicine will continue as an important patient care modality once COVID-19 becomes endemic. We explored provider and patients' perspectives on telemedicine implementation. Physicians from three specialties within the Department of Medicine of a single institution were electronically surveyed regarding their perceptions of satisfaction, benefits, and challenges of video visits, as well as the quality of interactions with patients. Patients were surveyed via telephone by the Survey Research Group at Cornell about participation in video visits, challenges encountered, perceived benefits, preferences for care, and overall satisfaction. Providers reported an overwhelmingly positive experience with video visits, with the vast majority agreeing that they were comfortable with the modality (98%) and that it was easy to interact with patients (92%). Most providers (72%) wanted to have more telemedicine encounters in the future. Key factors interfering with successful telemedicine encounters were technical challenges and insufficient technical support. Overall, patients also perceived video visits very positively regarding ease of communication and care received and had few privacy concerns. Some (10%-15%) patients expressed interest in receiving more technical support and training. There was a gradient of satisfaction with telemedicine across specialties with patients receiving weight management reporting more favorable responses while patients with lymphoma expressed more mixed responses. Both providers and patients found telemedicine to be an acceptable and useful modality to provide or receive medical care. The principal barrier to successful encounters was technical challenges.

Glycosphingolipid modulation may be a new approach to treat polycystic kidney disease. Blocking glucosylceramide accumulation with a glucosylceramide synthase inhibitor inhibits cyst formation in mouse models of the disease through inhibition of Akt-mediated signaling and by interfering with the cell cycle machinery. Polycystic kidney disease (PKD) represents a family of genetic disorders characterized by renal cystic growth and progression to kidney failure 1 . No treatment is currently available for people with PKD, although possible therapeutic interventions are emerging 2 , 3 , 4 , 5 , 6 , 7 , 8 . Despite genetic and clinical heterogeneity, PKDs have in common defects of cystic epithelia, including increased proliferation, apoptosis and activation of growth regulatory pathways 1 . Sphingolipids and glycosphingolipids are emerging as major regulators of these cellular processes 9 . We sought to evaluate the therapeutic potential for glycosphingolipid modulation as a new approach to treat PKD. Here we demonstrate that kidney glucosylceramide (GlcCer) and ganglioside GM3 levels are higher in human and mouse PKD tissue as compared to normal tissue, regardless of the causative mutation. Blockade of GlcCer accumulation with the GlcCer synthase inhibitor Genz-123346 effectively inhibits cystogenesis in mouse models orthologous to human autosomal dominant PKD ( Pkd1 conditional knockout mice) and nephronophthisis ( jck and pcy mice). Molecular analysis in vitro and in vivo indicates that Genz-123346 acts through inhibition of the two key pathways dysregulated in PKD: Akt protein kinase–mammalian target of rapamycin signaling and cell cycle machinery. Taken together, our data suggest that inhibition of GlcCer synthesis represents a new and effective treatment option for PKD.

Follicular lymphoma (FL) patients treated with firstline R‐CHOP who experience progression of disease (POD) within 2 years have a shorter survival than those who do not have POD within 2 years. Whether this observation holds for patients treated initially with biologic immunotherapy alone is unknown. We performed a retrospective analysis of 174 patients pooled from three frontline rituximab (R)‐based nonchemotherapy doublet trials: R‐galiximab (Anti‐CD80, CALGB 50402), R‐epratuzumab (Anti‐CD22, CALGB 50701), and R‐lenalidomide (CALGB 50803) to determine outcomes of early progressors and risk factors for early POD, defined as progression within 24 months from study entry. Twenty‐eight percent (48/174) of patients had early POD. After adjusting for the Follicular Lymphoma International Prognostic Index (FLIPI), patients with early POD from study entry had a worse OS compared with patients who did not progress within 2 years (HR = 4.33 (95% CI 1.50‐12.5), P = 0.007). For early POD, the 2‐year survival was 80% vs 99% for nonearly POD, and the 5‐year survival was 74% vs 90%, respectively. These findings suggest that the adverse survival of patients with early POD may be independent of initial treatment modality. In this combined analysis of three CALGB clinical trials, patients with early progression of follicular lymphoma following frontline immunotherapy doublets are at increased risk of death. PFS24 is a prognostic marker for overall survival in patients treated with rituximab‐containing immunotherapy.

Brentuximab vedotin is a drug immunoconjugate with an antibody targeting CD30, an antigen expressed mainly on Hodgkin's and anaplastic large-cell lymphomas, linked to a potent microtubule inhibitor. In a study involving 45 patients after relapse, 11 complete remissions were observed. Approximately 15 to 30% of patients with Hodgkin's lymphoma do not have a long-term remission with conventional therapy, 1 resulting in an estimated 1300 deaths annually in the United States alone. 2 Autologous hematopoietic stem-cell transplantation (ASCT) represents a potentially curative treatment for some patients with recurrent or progressive Hodgkin's lymphoma after failure of initial combination chemotherapy. Unfortunately, ASCT is only effective in approximately 50% of such patients. 3 , 4 Among those who have a relapse after ASCT, overall survival is 55% at 2 years and 32% at 5 years. 5 Because the incidence of Hodgkin's lymphoma peaks during young adulthood, these premature deaths . . .