Successful kinetic impact into an asteroid for planetary defence.

Although no known asteroid poses a threat to Earth for at least the next century, the catalogue of near-Earth asteroids is incomplete for objects whose impacts would produce regional devastation. Several approaches have been proposed to potentially prevent an asteroid impact with Earth by deflecting or disrupting an asteroid. A test of kinetic impact technology was identified as the highest-priority space mission related to asteroid mitigation.

PERIOD 2 regulates low-dose radioprotection via PER2/pGSK3β/β-catenin/Per2 loop.

During evolution, humans are acclimatized to the stresses of natural radiation and circadian rhythmicity. Radiosensitivity of mammalian cells varies in the circadian period and adaptive radioprotection can be induced by pre-exposure to low-level radiation (LDR). It is unclear, however, if clock proteins participate in signaling LDR radioprotection.

Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells.

Although the efficacy of cancer radiotherapy (RT) can be enhanced by targeted immunotherapy, the immunosuppressive factors induced by radiation on tumor cells remain to be identified. Here, we report that CD47-mediated anti-phagocytosis is concurrently upregulated with HER2 in radioresistant breast cancer (BC) cells and RT-treated mouse syngeneic BC. Co-expression of both receptors is more frequently detected in recurrent BC patients with poor prognosis.

CPT1A/2-Mediated FAO Enhancement-A Metabolic Target in Radioresistant Breast Cancer.

Tumor cells, including cancer stem cells (CSCs) resistant to radio- and chemotherapy, must enhance metabolism to meet the extra energy demands to repair and survive such genotoxic conditions. However, such stress-induced adaptive metabolic alterations, especially in cancer cells that survive radiotherapy, remain unresolved. In this study, we found that CPT1 (Carnitine palmitoyl transferase I) and CPT2 (Carnitine palmitoyl transferase II), a pair of rate-limiting enzymes for mitochondrial fatty acid transportation, play a critical role in increasing fatty acid oxidation (FAO) required for the cellular fuel demands in radioresistant breast cancer cells (RBCs) and radiation-derived breast cancer stem cells (RD-BCSCs).

Controlled Human Infection With Bordetella pertussis Induces Asymptomatic, Immunizing Colonization.

Background: Bordetella pertussis is among the leading causes of vaccine-preventable deaths and morbidity globally. Human asymptomatic carriage as a reservoir for community transmission of infections might be a target of future vaccine strategies, but has not been demonstrated. Our objective was to demonstrate that asymptomatic nasopharyngeal carriage of Bordetella pertussis is inducible in humans and to define the microbiological and immunological features of presymptomatic infection.

Treatment outcomes in HPV-negative oropharyngeal cancer: Surgery plus radiotherapy vs. definitive chemoradiotherapy.

We performed a retrospective study to compare clinical outcomes among 51 consecutively presenting patients-38 men and 13 women, aged 46 to 74 years (median: 57)-with locally advanced human papillomavirus (HPV)-negative oropharyngeal cancer who were treated with either primary surgery followed by postoperative radiotherapy (S/RT group; n = 22) or definitive chemoradiotherapy alone (CRT group; n = 29). Within the cohort, 45 patients reported a history of tobacco use, with a median intensity of 40 pack-years. In addition, 39 patients (76%) reported moderate to heavy alcohol use.

Shaving Is an Epiphenomenon of Type I and II Anti-CD20-Mediated Phagocytosis, whereas Antigenic Modulation Limits Type I Monoclonal Antibody Efficacy.

Rituximab is an anti-CD20 mAb used in the treatment of B cell malignancies. Loss of surface CD20 Ag from the surface of target cells is thought to be one mechanism governing resistance to rituximab, but how this occurs is not completely understood. Two explanations for this have been proposed: antigenic modulation whereby mAb:CD20 complexes are internalized in a B cell intrinsic process and shaving, in which mAb:CD20 complexes undergo trogocytic removal by effector cells, such as macrophages.

FcγRIIB-Independent Mechanisms Controlling Membrane Localization of the Inhibitory Phosphatase SHIP in Human B Cells.

SHIP is an important regulator of immune cell signaling that functions to dephosphorylate the phosphoinositide phosphatidylinositol 3,4,5-trisphosphate at the plasma membrane and mediate protein-protein interactions. One established paradigm for SHIP activation involves its recruitment to the phospho-ITIM motif of the inhibitory receptor FcγRIIB. Although SHIP is essential for the inhibitory function of FcγRIIB, it also has critical modulating functions in signaling initiated from activating immunoreceptors such as B cell Ag receptor.

Exposure Risks Among Children Undergoing Radiation Therapy: Considerations in the Era of Image Guided Radiation Therapy.

Recent improvements in toxicity profiles of pediatric oncology patients are attributable, in part, to advances in the field of radiation oncology such as intensity modulated radiation (IMRT) and proton therapy (IMPT). While IMRT and IMPT deliver highly conformal dose to targeted volumes, they commonly demand the addition of 2- or 3-dimensional imaging for precise positioning--a technique known as image guided radiation therapy (IGRT). In this manuscript we address strategies to further minimize exposure risk in children by reducing effective IGRT dose.

Influence of nuclear structure on the formation of radiation-induced lethal lesions.

Purpose The rejoining of fragmented nuclear DNA caused by ionizing radiation may lead to lethal chromosome rearrangements, such as rings or dicentrics. The clinically useful linear quadratic relationship between dose and cell survival has been interpreted as the generation of lethal lesions secondary to damage occurring in two separate chromosomes simultaneously (α component), or as potentially repairable separate events (β component). Here, the generation of such lesions is discussed, synthesizing existing knowledge with new insights gleaned from spatial proximity data made possible by high-throughput sequencing of chromosome conformation capture experiments.

Development and Characterization of Monoclonal Antibodies Specific for Mouse and Human Fcγ Receptors.

FcγRs are key regulators of the immune response, capable of binding to the Fc portion of IgG Abs and manipulating the behavior of numerous cell types. Through a variety of receptors, isoforms, and cellular expression patterns, they are able to fine-tune and direct appropriate responses. Furthermore, they are key determinants of mAb immunotherapy, with mAb isotype and FcγR interaction governing therapeutic efficacy.

Antibody modulation: Limiting the efficacy of therapeutic antibodies.

Monoclonal antibodies (mAb) have revolutionised the way in which we treat disease. From cancer to autoimmunity, antibody therapy has been responsible for some of the most impressive clinical responses observed in the last 2 decades. A key component of this success has been their generally low levels of toxicity, and unique mechanisms of action.

CDK1-Mediated SIRT3 Activation Enhances Mitochondrial Function and Tumor Radioresistance.

Tumor adaptive resistance to therapeutic radiation remains a barrier for further improvement of local cancer control. SIRT3, a member of the sirtuin family of NAD(+)-dependent protein deacetylases in mitochondria, promotes metabolic homeostasis through regulation of mitochondrial protein deacetylation and plays a key role in prevention of cell aging. Here, we demonstrate that SIRT3 expression is induced in an array of radiation-treated human tumor cells and their corresponding xenograft tumors, including colon cancer HCT-116, glioblastoma U87, and breast cancer MDA-MB231 cells.

SIRT3 Enhances Glycolysis and Proliferation in SIRT3-Expressing Gastric Cancer Cells.

SIRT3 is a key NAD+-dependent protein deacetylase in the mitochondria of mammalian cells, functioning to prevent cell aging and transformation via regulation of mitochondrial metabolic homeostasis. However, SIRT3 is also found to express in some human tumors; its role in these SIRT3-expressing tumor cells needs to be elucidated. This study demonstrated that the expression of SIRT3 was elevated in a group of gastric cancer cells compared to normal gastric epithelial cells.

Antagonistic human FcγRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo.

Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance.

CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection.

Mammalian cells are able to sense environmental oxidative and genotoxic conditions such as the environmental low-dose ionizing radiation (LDIR) present naturally on the earth's surface. The stressed cells then can induce a so-called radioadaptive response with an enhanced cellular homeostasis and repair capacity against subsequent similar genotoxic conditions such as a high dose radiation. Manganese superoxide dismutase (MnSOD), a primary mitochondrial antioxidant in mammals, has long been known to play a crucial role in radioadaptive protection by detoxifying O2(•-) generated by mitochondrial oxidative phosphorylation.

Activatory and inhibitory Fcγ receptors augment rituximab-mediated internalization of CD20 independent of signaling via the cytoplasmic domain.

Type I anti-CD20 mAb such as rituximab and ofatumumab engage with the inhibitory FcγR, FcγRIIb on the surface of B cells, resulting in immunoreceptor tyrosine-based inhibitory motif (ITIM) phosphorylation. Internalization of the CD20·mAb·FcγRIIb complex follows, the rate of which correlates with FcγRIIb expression. In contrast, although type II anti-CD20 mAb such as tositumomab and obinutuzumab also interact with and activate FcγRIIb, this interaction fails to augment the rate of CD20·mAb internalization, raising the question of whether ITIM phosphorylation plays any role in this process.

Estradiol induces gene proximity and MLL-MLLT3 fusion in an activation-induced cytidine deaminase-mediated pathway.

Epidemiological data have linked birth control formulations to an increased risk of infant acute leukemia involving MLL rearrangements. Reverse transcription polymerase chain reaction (RT-PCR) studies showed that 10 nM estradiol enhanced MLL transcription in addition to its common translocation partners, MLLT2 (AF4) and MLLT3 (AF9). The same concentration of estradiol triggered MLL and MLLT3 co-localization without affecting the interaction of genes located on the same chromosomes.

A systematic description of MLL fusion gene formation.

Rearrangements of the MLL gene involve multiple partners and are implicated in both therapy related acute leukemia [tAL] and infant acute leukemia. For these diseases, recently compiled clinical data confirms an elevated frequency of such breakpoints within a 4 kb tract between exon 11 and a region of structural instability adjacent to exon 12. Linked primarily to cases of tAL, interference with topoisomerase II activity may either contribute to the initial DNA lesion directly or indirectly by, for example, providing a physical block to transcription progression.

Detection of DNA double-strand breaks and chromosome translocations using ligation-mediated PCR and inverse PCR.

Current techniques for examining the global creation and repair of DNA double-strand breaks are restricted in their sensitivity, and such techniques mask any site-dependent variations in breakage and repair rate or fidelity. We present here a system for analyzing the fate of documented DNA breaks, using the MLL gene as an example, through application of ligation-mediated PCR. Here, a simple asymmetric double-stranded DNA adapter molecule is ligated to experimentally induced DNA breaks and subjected to seminested PCR using adapter- and gene-specific primers.

Competing causes of death and medical comorbidities among patients with human papillomavirus-positive vs human papillomavirus-negative oropharyngeal carcinoma and impact on adherence to radiotherapy.

Importance: Survival of patients with head and neck cancer can be affected by competing causes of mortality, as well as comorbidities that result in radiation treatment interruptions.

Objective: To discern how differences in preexisting medical and psychosocial comorbidities potentially influence adherence to radiation therapy according to human papillomavirus (HPV) status.

Design, Setting, And Participants: Retrospective analysis at a comprehensive cancer center of 162 consecutive patients with locally advanced squamous cell carcinoma of the oropharynx treated with primary chemoradiation (n = 95) or primary surgery followed by adjuvant radiation (n = 67).

Inhibitory FcγRIIb (CD32b) becomes activated by therapeutic mAb in both cis and trans and drives internalization according to antibody specificity.

A major feature that distinguishes type I from type II anti-CD20 monoclonal antibodies (mAbs) and reduces their therapeutic efficacy is the tendency to internalize from the cell surface. We have shown previously that the extent of internalization correlates with the capacity of type I mAb to simultaneously engage both CD20 and the inhibitory Fcγ receptor, FcγRIIb, in a bipolar configuration. Here, we investigated whether mAbs directed at other B-cell surface receptors also engaged FcγRIIb and whether this interaction promoted internalization.

Definitive radiation therapy without chemotherapy for human papillomavirus-positive head and neck cancer.

Background: To report a single institutional experience with definitive radiation therapy alone for human papillomavirus (HPV)-positive head and neck cancer.

Methods: A total of 67 patients were treated by radiation therapy alone to a median dose of 70 Gy (range, 66-72 Gy) for squamous cell carcinoma of the head and neck. Paraffin-embedded, formalin-fixed pretreatment tumor tissues were used to establish HPV-positivity using standardized techniques of immunohistochemistry for p16 and polymerase chain reaction for HPV.

CyclinB1/Cdk1 phosphorylates mitochondrial antioxidant MnSOD in cell adaptive response to radiation stress.

Manganese superoxide dismutase (MnSOD), a major antioxidant enzyme within the mitochondria, is responsible for the detoxification of free radicals generated by cellular metabolism and environmental/therapeutic irradiation. Cell cycle-dependent kinase Cdk1, along with its regulatory partner CyclinB1, plays important roles in the regulation of cell cycle progression as well as in genotoxic stress response. Herein, we identified the presence of the minimal Cdk1 phosphorylation consensus sequence ([S/T]-P; Ser106) in human MnSOD, suggesting Cdk1 as a potential upstream kinase of MnSOD.