The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors

CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.     

Acquisition of 1,000 eubacterial genes physiologically transformed a methanogen at the origin of Haloarchaea

Archaebacterial halophiles (Haloarchaea) are oxygen-respiring heterotrophs that derive from methanogens—strictly anaerobic, hydrogen-dependent autotrophs. Haloarchaeal genomes are known to have acquired, via lateral gene transfer (LGT), several genes from eubacteria, but it is yet unknown how many genes the Haloarchaea acquired in total and, more importantly, whether independent haloarchaeal lineages acquired their genes in parallel, or as a single acquisition at the origin of the group. Here we have studied 10 haloarchaeal and 1,143 reference genomes and have identified 1,089 haloarchaeal gene families that were acquired by a methanogenic recipient from eubacteria. The data suggest that these genes were acquired in the haloarchaeal common ancestor, not in parallel in independent haloarchaeal lineages, nor in the common ancestor of haloarchaeans and methanosarcinales. The 1,089 acquisitions include genes for catabolic carbon metabolism, membrane transporters, menaquinone biosynthesis, and complexes I–IV of the eubacterial respiratory chain that functions in the haloarchaeal membrane consisting of diphytanyl isoprene ether lipids. LGT on a massive scale transformed a strictly anaerobic, chemolithoautotrophic methanogen into the heterotrophic, oxygen-respiring, and bacteriorhodopsin-photosynthetic haloarchaeal common ancestor.Halophilic archaebacteria (Haloarchaea) require concentrated salt solutions for survival and can inhabit saturated brine environments such as salt lakes, the Dead Sea, and salterns (1). In rRNA and phylogenomic analyses of informational genes, Haloarchaea always branch well within the methanogens (2–4). Haloarchaea can thus be seen as deriving from methanogen ancestors, but the physiology of methanogens and halophiles could hardly be more different. Methanogens are strict anaerobes, most species are lithoautotrophs that use electrons from H₂ to reduce CO₂ to methane (obligate hydrogenotrophic methanogens), thereby generating a chemiosmotic ion gradient for ATP synthesis in their energy metabolism, although some species can generate methane from reduced C₁ compounds, or acetate in the case of aceticlastic forms (5–7). Their carbon metabolism involves the Wood–Ljungdahl (acetyl-CoA) pathway of CO₂ fixation (5–7). In contrast, Haloarchaea are obligate heterotrophs that typically use O₂ as the terminal acceptor of their electron transport chain, although many can also use alternative electron acceptors such as nitrate in addition to light harnessing via a bacteriorhodopsin-based proton pumping system (8). The evolutionary nature of that radical physiological transformation from anaerobic chemolithoautotroph to aerobic heterotroph is of interest.Many individual reports document that lateral gene transfer (LGT) from eubacteria was involved in the origin of at least some components of haloarchaeal metabolism. These include the operon for gas vesicle formation, which allows Haloarchaea to remain in surface waters (9), the newly identified methylaspartate cycle of acetyl-CoA oxidation (10), various components of the haloarchaeal aerobic respiratory chain (11–18), and proteins involved in the assembly of FeS clusters (19). The sequencing of the first haloarchaeal genome over a decade ago identified some eubacterial genes that possibly could have been acquired by lateral gene transfer (11, 20), and whereas substantial data that would illuminate the origin of haloarchaeal physiology have accumulated since then, those data have not been subjected to comparative evolutionary analysis. Investigating the role of the environment in haloarchaeal genome evolution, Rhodes et al. (21) recently showed that Haloarchaea are indeed far more likely to acquire genes from other halophiles, but they did not address the issues at the focus of our present investigation, namely: How many eubacterial acquisitions are present in haloarchaeal genomes? How was the physiological transformation of methanogens to Haloarchaea affected by LGT? Do those acquisitions trace to the haloarchaeal common ancestor as a single acquisition or not?To discern whether the eubacterial genes in haloarchaeal genomes are the result of multiple independent transfers in individual lineages or the result of a single ancient mass acquisition, here we have analyzed 10 sequenced haloarchaeal genomes—Haloarcula marismortui (22), Halobacterium salinarum (23), Halobacterium sp. (20), Halomicrobium mukohataei (24), Haloquadratum walsbyi (25), Halorhabdus utahensis (26), Halorubrum lacusprofundi (27), Natrialba magadii (28), Natronomonas pharaonis (29), and Haloterrigena turkmmenica (30)—in the context of 65 other archaebacterial and >1,000 eubacterial reference genomes.     

The increased risk for pneumocystis pneumonia in patients receiving rituximab-CHOP-14 can be prevented by the administration of trimethoprim/sulfamethoxazole: a single-center experience

Recent studies suggest an increased risk for Pneumocystis jirovecii pneumonia (PJP) in adults receiving short-interval rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) therapy for diffuse large cell B cell lymphoma (DLBCL). This retrospective study evaluates precise PJP incidence and the efficacy of anti-PJP prophylaxis in DLBCL. Patients with DLBCL, aged ≥18 years and treated between December 2004 and December 2010, were included. Details of treatment-related respiratory infections, focusing on PJP incidence, risk factors and prophylaxis, were assessed. A total of 132 patients were analyzed; 47 were treated with rituximab-CHOP therapy every 21 days (R-CHOP-21) and 85 were treated every 14 days (R-CHOP-14). The incidence of treatment-related respiratory infections was higher in patients receiving R-CHOP-14. PJP was diagnosed in 5 patients: 4 in the R-CHOP-14 (6.6%) and 1 in the R-CHOP-21 cohort (2.6%), using triplex polymerase chain reaction (PCR) for PJ in bronchoalveolar fluid. None of the patients receiving P.jirovecii prophylaxis (n = 33) developed PJP, compared with 6.6% of those treated with R-CHOP-14 without such prophylaxis. An older age and R-CHOP administered every 14 rather than every 21 days increased the PJP risk. Trimethoprim/sulfamethoxazole prophylaxis is found to be highly efficient in preventing this life-threatening complication and, therefore, should be recommended for patients receiving the R-CHOP-14 regimen.     

Allogeneic stem cell transplantation for patients with chronic myeloid leukemia: Risk stratified approach with a long-term follow-up

The use of allogeneic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) was almost abandoned in recent years for very effective targeted therapy with tyrosine kinase inhibitors (TKIs). However, approximately one third of patients still need another treatment including SCT. 38 consecutive CML patients were treated (most in preimatinib era) with allogeneic SCT, using partial T cell depletion (TCD) and preemptive donor lymphocyte infusion (DLI), without post‐transplant graft‐versus‐host disease (GvHD) prophylaxis. Conditioning included busulfan, cyclophosphamide, antithymocytic globulin, and fludarabine followed by donor stem cell transfusion. With a median follow up of 90.5 months (1–134), 32 patients are alive. 97% engrafted. 5‐year leukemia free survival (LFS) and overall survival (OS) were 78.95% and 84.2%, respectively. All patients are in major molecular remission and 78% in complete molecular remission. Transplant‐related mortality (TRM) was 13%. Twenty‐four patients received DLI for residual disease. Acute GvHD, mostly Grades I‐II, occurred in 18% of patients post‐transplant and in 24% of patients receiving DLI. In conclusion, the risk‐adapted approach using only partial TCD and preemptive escalated dose of DLI precluded the need for immunosuppressive medications and reduced the risk of significant GvHD without compromising engraftment and long‐term disease control. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.     

Vestibular evoked myogenic potentials and habituation to seasickness

Objective

Seasickness may impose severe limitations on the performance of ships’ crew. Cervical vestibular evoked myogenic potentials (cVEMP) assess the function of the saccule, the organ responsible for monitoring vertical linear acceleration, which has been found to be the most provocative motion stimulus in the evolution of motion sickness. We used the cVEMP test in a prospective evaluation of susceptibility and habituation to seasickness.

Methods

Forty-six naval recruits underwent the cVEMP test before exposure to sea conditions. After 6 months’ sailing experience, participants completed a questionnaire evaluating their initial and current seasickness severity. Based on their most recent experience, subjects were divided into three groups: non-vomiting non-habituating (NV-NH), vomiting (V), and non-vomiting habituating (NV-H).

Results

Statistically significant lower thresholds for cVEMP were found in subjects who habituated to sea conditions (NV-H), compared with those remaining severely susceptible (V) (77.0 dB HL vs. 84.9 dB HL; p < 0.01).

Conclusions

The ability to produce the cVEMP at lower thresholds represents a broader dynamic range, in which the reflex can respond to a wider array of stimuli amplitudes.

Significance

The present study demonstrates the potential of the cVEMP test for predicting future habituation to seasickness.     

Diffuse axonal injury in mild traumatic brain injury: a 3D multivoxel proton MR spectroscopy study

Since mild traumatic brain injury (mTBI) often leads to neurological symptoms even without clinical MRI findings, our goal was to test whether diffuse axonal injury is quantifiable with multivoxel proton MR spectroscopic imaging (¹H-MRSI). T1- and T2-weighted MRI images and three-dimensional ¹H-MRSI (480 voxels over 360 cm³, about 30 % of the brain) were acquired at 3 T from 26 mTBI patients (mean Glasgow Coma Scale score 14.7, 18–56 years old, 3–55 days after injury) and 13 healthy matched contemporaries as controls. The N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) concentrations and gray-matter/white-matter (GM/WM) and cerebrospinal fluid fractions were obtained in each voxel. Global GM and WM absolute metabolic concentrations were estimated using linear regression, and patients were compared with controls using two-way analysis of variance. In patients, mean NAA, Cr, Cho and mI concentrations in GM (8.4 ± 0.7, 6.9 ± 0.6, 1.3 ± 0.2, 5.5 ± 0.6 mM) and Cr, Cho and mI in WM (4.8 ± 0.5, 1.4 ± 0.2, 4.6 ± 0.7 mM) were not different from the values in controls. The NAA concentrations in WM, however, were significantly lower in patients than in controls (7.2 ± 0.8 vs. 7.7 ± 0.6 mM, p = 0.0125). The Cho and Cr levels in WM of patients were positively correlated with time since mTBI. This ¹H-MRSI approach allowed us to ascertain that early mTBI sequelae are (1) diffuse (not merely local), (2) neuronal (not glial), and (3) in the global WM (not GM). These findings support the hypothesis that, similar to more severe head trauma, mTBI also results in diffuse axonal injury, but that dysfunction rather than cell death dominates shortly after injury.