DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the ...interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.
Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies.
Cancer cells from a primary tumor can disseminate to other tissues, remaining dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to ...awaken, resume proliferating, and develop into metastases. Studying mouse models, we found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Sustained inflammation induced the formation of neutrophil extracellular traps (NETs), and these were required for awakening dormant cancer. Mechanistic analysis revealed that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved laminin. The proteolytically remodeled laminin induced proliferation of dormant cancer cells by activating integrin α3β1 signaling. Antibodies against NET-remodeled laminin prevented awakening of dormant cells. Therapies aimed at preventing dormant cell awakening could potentially prolong the survival of cancer patients.
Cellulose is inherently resistant to breakdown, and the native crystalline structure (cellulose I) of cellulose is considered to be one of the major factors limiting its potential in terms of ...cost-competitive lignocellulosic biofuel production. Here we report the impact of ionic liquid pretreatment on the cellulose crystalline structure in different feedstocks, including microcrystalline cellulose (Avicel), switchgrass ( Panicum virgatum ), pine ( Pinus radiata ), and eucalyptus ( Eucalyptus globulus ), and its influence on cellulose hydrolysis kinetics of the resultant biomass. These feedstocks were pretreated using 1-ethyl-3-methyl imidazolium acetate (C2mimOAc) at 120 and 160 °C for 1, 3, 6, and 12 h. The influence of the pretreatment conditions on the cellulose crystalline structure was analyzed by X-ray diffraction (XRD). On a larger length scale, the impact of ionic liquid pretreatment on the surface roughness of the biomass was determined by small-angle neutron scattering (SANS). Pretreatment resulted in a loss of native cellulose crystalline structure. However, the transformation processes were distinctly different for Avicel and for the biomass samples. For Avicel, a transformation to cellulose II occurred for all processing conditions. For the biomass samples, the data suggest that pretreatment for most conditions resulted in an expanded cellulose I lattice. For switchgrass, first evidence of cellulose II only occurred after 12 h of pretreatment at 120 °C. For eucalyptus, first evidence of cellulose II required more intense pretreatment (3 h at 160 °C). For pine, no clear evidence of cellulose II content was detected for the most intense pretreatment conditions of this study (12 h at 160 °C). Interestingly, the rate of enzymatic hydrolysis of Avicel was slightly lower for pretreatment at 160 °C compared with pretreatment at 120 °C. For the biomass samples, the hydrolysis rate was much greater for pretreatment at 160 °C compared with pretreatment at 120 °C. The result for Avicel can be explained by more complete conversion to cellulose II upon precipitation after pretreatment at 160 °C. By comparison, the result for the biomass samples suggests that another factor, likely lignin−carbohydrate complexes, also impacts the rate of cellulose hydrolysis in addition to cellulose crystallinity.
Golden retriever dogs have been reported to have an increased prevalence of cancer compared to other breeds. There is also controversy over the effect spay or neuter status might have on longevity ...and the risk for developing cancer. The electronic medical records system at an academic center was searched for all dogs who had a necropsy exam from 1989-2016. 9,677 canine necropsy examinations were completed of which 655 were golden retrievers. Age was known for 652 with a median age of death 9.15 years. 424 of the 652 (65.0%) were determined to have died because of cancer. The median age for dying of a cause other than cancer was 6.93 years while those dying of cancer had a median age of 9.83 years (p<0.0001). There was no significant difference in the proportion of intact males and castrated males dying of cancer (p = 0.43) but a greater proportion of spayed females died of cancer compared to intact females (p = 0.001). Intact female dogs had shorter life spans than spayed female dogs (p<0.0001), but there were no differences between intact and castrated males. Intriguingly, being spayed or neutered did not affect the risk of a cancer related death but increasing age did. The most common histologic diagnosis found in golden retrievers dying of cancer was hemangiosarcoma (22.64%) followed by lymphoid neoplasia (18.40%). Overall golden retriever dogs have a substantial risk of cancer related mortality in a referral population and age appears to have a larger effect on cancer related mortality than reproductive status.
Ionic liquids (ILs) have been shown to affect cellulose crystalline structure in lignocellulosic biomass during pretreatment. A systematic investigation of the swelling and dissolution processes ...associated with IL pretreatment is needed to better understand cellulose structural transformation. In this work, 3–20 wt % microcrystalline cellulose (Avicel) solutions were treated with 1-ethyl-3-methylimidazolium acetate (C2mimOAc) and a mixture of C2mimOAc with the nonsolvent dimethyl sulfoxide (DMSO) at different temperatures. The dissolution process was slowed by decreasing the temperature and increasing cellulose loading, and was further retarded by addition of DMSO, enabling in-depth examination of the intermediate stages of dissolution. Results show that the cellulose I lattice expands and distorts prior to full dissolution in C2mimOAc and that upon precipitation the former structure leads to a less ordered intermediate structure, whereas fully dissolved cellulose leads to a mixture of cellulose II and amorphous cellulose. Enzymatic hydrolysis was more rapid for the intermediate structure (crystallinity = 0.34) than for cellulose II (crystallinity = 0.54).
Neuroprediction of future rearrest Aharoni, Eyal; Vincent, Gina M.; Harenski, Carla L. ...
Proceedings of the National Academy of Sciences - PNAS,
04/2013, Letnik:
110, Številka:
15
Journal Article
Recenzirano
Odprti dostop
Identification of factors that predict recurrent antisocial behavior is integral to the social sciences, criminal justice procedures, and the effective treatment of high-risk individuals. Here we ...show that error-related brain activity elicited during performance of an inhibitory task prospectively predicted subsequent rearrest among adult offenders within 4 y of release (N = 96). The odds that an offender with relatively low anterior cingulate activity would be rearrested were approximately double that of an offender with high activity in this region, holding constant other observed risk factors. These results suggest a potential neurocognitive biomarker for persistent antisocial behavior.
Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing ∼1,000 breast cancer samples, we confirmed this association and ...established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.
As of 10 April 2020, New York State had 180,458 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 9,385 reported deaths. Patients with cancer comprised 8.4% of deceased ...individuals
. Population-based studies from China and Italy suggested a higher coronavirus disease 2019 (COVID-19) death rate in patients with cancer
, although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-19
. This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. From 10 March to 7 April 2020, 423 cases of symptomatic COVID-19 were diagnosed at Memorial Sloan Kettering Cancer Center (from a total of 2,035 patients with cancer tested). Of these, 40% were hospitalized for COVID-19, 20% developed severe respiratory illness (including 9% who required mechanical ventilation) and 12% died within 30 d. Age older than 65 years and treatment with immune checkpoint inhibitors (ICIs) were predictors for hospitalization and severe disease, whereas receipt of chemotherapy and major surgery were not. Overall, COVID-19 in patients with cancer is marked by substantial rates of hospitalization and severe outcomes. The association observed between ICI and COVID-19 outcomes in our study will need further interrogation in tumor-specific cohorts.
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