A uniformly ergodic Gibbs sampler for Bayesian survival analysis

Finite sample inference for Cox models is an important problem in many settings, such as clinical trials. Bayesian procedures provide a means for finite sample inference and incorporation of prior information if MCMC algorithms and posteriors are well behaved. On the other hand, estimation procedures should also retain inferential properties in high dimensional settings. In addition, estimation procedures should be able to incorporate constraints and multilevel modeling such as cure models and frailty models in a straightforward manner. In order to tackle these modeling challenges, we propose a uniformly ergodic Gibbs sampler for a broad class of convex set constrained multilevel Cox models. We develop two key strategies. First, we exploit a connection between Cox models and negative binomial processes through the Poisson process to reduce Bayesian computation to iterative Gaussian sampling. Next, we appeal to sufficient dimension reduction to address the difficult computation of nonparametric baseline hazards, allowing for the collapse of the Markov transition operator within the Gibbs sampler based on sufficient statistics. We demonstrate our approach using open source data and simulations

Reconsidering Israel's Past

Un des chefs de file de la nouvelle histoire en Israël, qu'on qualifie également de post-sioniste, met en question la rhétorique sionisto-nationaliste qui, pour des raisons idéologiques, quitte à faire une lecture des faits souvent unilatérale, a produit une historiographie conforme à ses vœux. L'ouverture de nouveaux fonds d'archives, l'évolution des mentalités en Israël, l'affaiblissement de l'idéologie sioniste font qu'aujourd'hui s'impose dans certains cercles intellectuels une nouvelle grille de lecture des événements, notamment ceux qui concernent les Arabes au premier chef

Reconsidering Israel's Past

Un des chefs de file de la nouvelle histoire en Israël, qu'on qualifie également de post-sioniste, met en question la rhétorique sionisto-nationaliste qui, pour des raisons idéologiques, quitte à faire une lecture des faits souvent unilatérale, a produit une historiographie conforme à ses vœux. L'ouverture de nouveaux fonds d'archives, l'évolution des mentalités en Israël, l'affaiblissement de l'idéologie sioniste font qu'aujourd'hui s'impose dans certains cercles intellectuels une nouvelle grille de lecture des événements, notamment ceux qui concernent les Arabes au premier chef

Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells

AbstractT-cell recovery following myeloablative preparatory regimens and cord blood transplantation in adult patients gen erally occurs between 1 and 3 years following allogeneic bone marrow transplantation. T-cell reconstitution may involve thymic education of donor-derived precursors or peripheral expansion of mature T-cells transferred in the graft. We measured quantitative and qualitative immunologic reconstitution, T-cell receptor spectratyping, and T-cell receptor excision circle (TREC) levels in adult recipients of umbilical cord blood transplants following a novel nonmyeloablative regimen. These results were compared to previously published results of similar patients receiving a myeloablative regimen and cord blood stem cells. With small numbers of patients treated so far, T-cells (CD3+) reached normal levels in adults 6 to 12 months following nonmyeloablative transplantation compared with 24 months in adults receiving a myeloablative regimen. At 12 months after transplantation, the numbers of phenotypically naive (CD45RA) T-cells were higher in those receiving the nonmyeloablative regimen. The T-cell repertoire in cord blood recipients treated with a nonmyeloablative regimen was markedly more diverse and robust compared with the repertoire in those receiving the myeloablative regimen at similar time points. TRECs (which are generated within the thymus and identify new thymic emigrants and those that have not divided) were detected 12 months after transplantation in the nonmyeloablative recipients, whereas TRECs were not detected in adults until 18 to 24 months in those receiving myeloablative regimens. Thus, in adults receiving a nonmyeloablative preparatory regimen, the quantitative and qualitative recovery of T-cells occurs through rapid peripheral expansion. The ability of patients receiving a nonmyeloablative regimen to recover within a few months suggests that the peripheral niches in which T-cells can proliferate are preserved in these patients compared to those receiving ablative regimens. Moreover, the presence of TREC-positive cells within 1 year suggests that thymic recovery is likewise accelerated in non myeloablative compared to myeloablative regimens.Biol Blood Marrow Transplant 2002;8(5):249-56

Phase II Trial of MEDI0457 and Durvalumab for Patients With Recurrent/Metastatic Human Papillomavirus-Associated Cancers

BACKGROUND: Human papillomavirus (HPV) types 16/18 drive oncogenesis for most patients with cervical, anal, and penile cancers. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 HPV-16/18 viral oncogenes and IL-12 adjuvant, is safe and provokes an immune response against E6/E7. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for patients with HPV-associated cancers. METHODS: Patients with recurrent/metastatic, treatment-refractory HPV-16/18 cervical cancer, or rare HPV-associated (anal and penile) cancers were eligible. Prior immune checkpoint inhibition was not permitted. Patients received MEDI0457 7 mg intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks. The primary endpoint was overall response (RECIST 1.1). In this Simon two-stage phase 2 trial (Ho: p \u3c 0.15; Ha: p ≥ 0.35), ≥2 responses were needed in both cervical and non-cervical cohorts during the first stage for the trial to proceed to stage 2 with an additional 25 patients (34 total) enrolled. RESULTS: Twenty-one patients (12 cervical, 7 anal, and 2 penile) were evaluable for toxicity and 19 for response Overall response rate was 21% (95% CI, 6%-46%) among evaluable patients. Disease control rate was 37% (95% CI, 16%-62%). Median duration of response among responders was 21.8 months (95% CI, 9.7%-not estimable). Median progression-free survival was 4.6 months (95% CI, 2.8%-7.2%). Median overall survival was 17.7 months (95% CI, 7.6%-not estimable). Grades 3-4 treatment-related adverse events occurred in 6 (23%) participants. CONCLUSIONS: The combination of MEDI0457 and durvalumab demonstrated acceptable safety and tolerability in patients with advanced HPV-16/18 cancers. The low ORR among patients with cervical cancer led to study discontinuation despite a clinically meaningful disease control rate

Differential Spatial Gene and Protein Expression Associated with Recurrence Following Chemoradiation for Localized Anal Squamous Cell Cancer

The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA

Association of Prediagnosis Obesity and Postdiagnosis Aspirin With Survival From Stage IV Colorectal Cancer

IMPORTANCE: The potential relationship between obesity and colorectal cancer (CRC) outcome is poorly understood in patients with late-stage disease. Increased body mass index may negate aspirin use for cancer prevention, but its role as a factor on the effectiveness of postdiagnosis aspirin use is unclear. OBJECTIVE: To evaluate how prediagnosis obesity and postdiagnosis aspirin use may be associated with overall survival in patients with late-stage colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used self-reported data from patients with metastatic or treatment-refractory disease who consented to a clinical protocol at MD Anderson Cancer Center, a large US cancer treatment center. Patients were enrolled between 2010 and 2018 and followed up for mortality through July 2020. Analyses were conducted through March 2022. EXPOSURES: Body mass index in the decade prior to initial diagnosis and regular aspirin use at survey completion. MAIN OUTCOMES AND MEASURES: Overall survival was measured from stage IV diagnosis until death or last follow-up. Cox proportional hazards models were constructed to estimate associations of prediagnosis obesity and postdiagnosis aspirin use with overall survival. RESULTS: Of 656 patients included in this analysis, 280 (42.7%) were women, 135 (20.6%) were diagnosed with CRC before age 45 years, 414 (63.1%) were diagnosed between ages 45 and 65 years, and 107 (16.3%) were diagnosed at 65 years or older; 105 patients (16.0%) were Black or Hispanic, and 501 (76.4%) were non-Hispanic White. Controlling for age, sex, race, stage at initial diagnosis, and weight change between prediagnosis and survey date, patients with obesity in the decade prior to CRC diagnosis had significantly higher likelihood of death (hazard ratio, 1.45; 95% CI, 1.11-1.91) compared with those with normal prediagnosis body mass index. Furthermore, only patients with normal prediagnosis body mass index experienced significant survival benefit with postdiagnosis aspirin use (hazard ratio, 0.59; 95% CI, 0.39-0.90). CONCLUSIONS AND RELEVANCE: In this cross-sectional study, our findings suggest potentially differential tumor development in the long-term physiologic host environment of obesity. Confirmation and further evaluation are needed to determine whether prediagnosis body mass index may be used to estimate the benefit from postdiagnosis aspirin use

Abiotic Input of Fixed Nitrogen by Bolide Impacts to Gale Crater During the Hesperian : Insights From the Mars Science Laboratory

We acknowledge the NASA Mars Science Laboratory Program, Centre National d'Études Spatiales, the Universidad Nacional Autónoma de México (PAPIIT IN109416, IN111619, and PAPIME PE103216), and the Consejo Nacional de Ciencia y Tecnología de México (CONACyT 220626) for their support. We thank Fred Calef for constructing Figure 4 and appreciate the interest and support received from John P. Grotzinger and Joy A. Crisp throughout the Curiosity mission. The authors are grateful to the SAM and MSL teams for successful operation of the SAM instrument and the Curiosity rover. The data used in this paper are listed in the supporting information, figures, and references. SAM Data contained in this paper are publicly available through the NASA Planetary Data System at http://pds‐geosciences.wustl.edu/missions/msl/sam.htm. We would like to express gratitude to Pierre‐Yves Meslin from the Research Institute in Astrophysics and Planetology at Toulouse, France, and five anonymous reviewers whose comments/suggestions on earlier drafts helped improve and clarify this manuscript. The authors declare no conflicts of interests.Peer reviewedPublisher PD

Notes for genera: basal clades of Fungi (including Aphelidiomycota, Basidiobolomycota, Blastocladiomycota, Calcarisporiellomycota, Caulochytriomycota, Chytridiomycota, Entomophthoromycota, Glomeromycota, Kickxellomycota, Monoblepharomycota, Mortierellomycota, Mucoromycota, Neocallimastigomycota, Olpidiomycota, Rozellomycota and Zoopagomycota)

Compared to the higher fungi (Dikarya), taxonomic and evolutionary studies on the basal clades of fungi are fewer in number. Thus, the generic boundaries and higher ranks in the basal clades of fungi are poorly known. Recent DNA based taxonomic studies have provided reliable and accurate information. It is therefore necessary to compile all available information since basal clades genera lack updated checklists or outlines. Recently, Tedersoo et al. (MycoKeys 13:1--20, 2016) accepted Aphelidiomycota and Rozellomycota in Fungal clade. Thus, we regard both these phyla as members in Kingdom Fungi. We accept 16 phyla in basal clades viz. Aphelidiomycota, Basidiobolomycota, Blastocladiomycota, Calcarisporiellomycota, Caulochytriomycota, Chytridiomycota, Entomophthoromycota, Glomeromycota, Kickxellomycota, Monoblepharomycota, Mortierellomycota, Mucoromycota, Neocallimastigomycota, Olpidiomycota, Rozellomycota and Zoopagomycota. Thus, 611 genera in 153 families, 43 orders and 18 classes are provided with details of classification, synonyms, life modes, distribution, recent literature and genomic data. Moreover, Catenariaceae Couch is proposed to be conserved, Cladochytriales Mozl.-Standr. is emended and the family Nephridiophagaceae is introduced