Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.

The ecology of human-caused mortality for a protected large carnivore.

Mitigating human-caused mortality for large carnivores is a pressing global challenge for wildlife conservation. However, mortality is almost exclusively studied at local (within-population) scales creating a mismatch between our understanding of risk and the spatial extent most relevant to conservation and management of wide-ranging species. Here, we quantified mortality for 590 radio-collared mountain lions statewide across their distribution in California to identify drivers of human-caused mortality and investigate whether human-caused mortality is additive or compensatory. Human-caused mortality, primarily from conflict management and vehicles, exceeded natural mortality despite mountain lions being protected from hunting. Our data indicate that human-caused mortality is additive to natural mortality as population-level survival decreased as a function of increasing human-caused mortality and natural mortality did not decrease with increased human-caused mortality. Mortality risk increased for mountain lions closer to rural development and decreased in areas with higher proportions of citizens voting to support environmental initiatives. Thus, the presence of human infrastructure and variation in the mindset of humans sharing landscapes with mountain lions appear to be primary drivers of risk. We show that human-caused mortality can reduce population-level survival of large carnivores across large spatial scales, even when they are protected from hunting.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Pathological concordance rate and outcomes by subtype in advanced papillary renal cell carcinoma.

OBJECTIVE: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. METHODS: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression-free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. RESULTS: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. CONCLUSIONS: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. PATIENT SUMMARY: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial.

A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions.

Active mutations in the RAS genes are found in ∼30% of human cancers. Although thought to have overlapping functions, RAS isoforms show preferential activation in human tumors, which prompted us to employ a comparative and quantitative proteomics approach to generate isoform-specific and nucleotide-dependent interactomes of the four RAS isoforms, KRAS4A, KRAS4B, HRAS, and NRAS. Many isoform-specific interacting proteins were identified, including HRAS-specific CARM1 and CHK1 and KRAS-specific PIP4K2C and IPO7. Comparing the interactomes of WT and constitutively active G12D mutant of RAS isoforms, we identified several potential previously unknown effector proteins of RAS, one of which was recently reported while this article was in preparation, RADIL. These interacting proteins play important roles as knockdown or pharmacological inhibition leads to potent inhibition of cancer cells. The HRAS-specific interacting protein CARM1 plays a role in HRAS-induced senescence, with CARM1 knockdown or inhibition selectively increasing senescence in HRAS-transformed cells but not in KRAS4B-transformed cells. By revealing new isoform-specific and nucleotide-dependent RAS interactors, the study here provides insights to help understand the overlapping functions of the RAS isoforms.

Vaccine target and carrier molecule nontypeable Haemophilus influenzae protein D dimerizes like the close Escherichia coli GlpQ homolog but unlike other known homolog dimers.

We have determined the 1.8 Å X-ray crystal structure of nonlipidated (i.e., N-terminally truncated) nontypeable Haemophilus influenzae (NTHi; H. influenzae) protein D. Protein D exists on outer membranes of H. influenzae strains and acts as a virulence factor that helps invade human cells. Protein D is a proven successful antigen in animal models to treat obstructive pulmonary disease (COPD) and otitis media (OM), and when conjugated to polysaccharides also has been used as a carrier molecule for human vaccines, for example in GlaxoSmithKline Synflorix™. NTHi protein D shares high sequence and structural identify to the Escherichia coli (E. coli) glpQ gene product (GlpQ). E. coli GlpQ is a glycerophosphodiester phosphodiesterase (GDPD) with a known dimeric structure in the Protein Structural Database, albeit without an associated publication. We show here that both structures exhibit similar homodimer organization despite slightly different crystal lattices. Additionally, we have observed both the presence of weak dimerization and the lack of dimerization in solution during size exclusion chromatography (SEC) experiments yet have distinctly observed dimerization in native mass spectrometry analyses. Comparison of NTHi protein D and E. coli GlpQ with other homologous homodimers and monomers shows that the E. coli and NTHi homodimer interfaces are distinct. Despite this distinction, NTHi protein D and E. coli GlpQ possess a triose-phosphate isomerase (TIM) barrel domain seen in many of the other homologs. The active site of NTHi protein D is located near the center of this TIM barrel. A putative glycerol moiety was modeled in two different conformations (occupancies) in the active site of our NTHi protein D structure and we compared this to ligands modeled in homologous structures. Our structural analysis should aid in future efforts to determine structures of protein D bound to substrates, analog intermediates, and products, to fully appreciate this reaction scheme and aiding in future inhibitor design.

Domain-Specific Outcome Measures in Clinical Trials of Therapies Promoting Stroke Recovery: A Suggested Blueprint.

Different deficits recover to different degrees and with different time courses after stroke, indicating that plasticity differs across the brain's neural systems after stroke. To capture these differences, domain-specific outcome measures have received increased attention. Such measures have potential advantages over global outcome scales, which combine recovery across many domains into a single score and so blur the ability to capture individual measures of stroke recovery. Use of a global end point to rate disability can overlook substantial recovery in specific domains, such as motor or language, and may not differentiate between good and poor recovery for specific neurological domains. In light of these points, a blueprint is proposed for using domain-specific outcome measures in stroke recovery trials. Key steps include selecting a domain in the context of preclinical data, picking a domain-specific clinical trial end point, anchoring inclusion criteria to this end point, scoring this end point both before and after treatment, and then pursuing regulatory approval on the basis of the domain-specific results. This blueprint is intended to foster clinical trials that, by using domain-specific end points, are able to demonstrate favorable results in clinical trials of therapies that promote stroke recovery.

A circovirus and cycloviruses identified in feces of bobcats (Lynx rufus) in California.

Viruses in the family Circoviridae have small circular single-stranded DNA (ssDNA) genomes. Circoviruses are known to infect a wide variety of animals, with notable disease pathology in psittacine (psittacine beak and feather disease) and porcine (postweaning multisystemic wasting syndrome) species. There is still a dearth of research investigating circoviruses associated with felid species. In six fecal samples collected from bobcats (Lynx rufus) in California from 2010 to 2011, we identified six viruses belonging to the genera Circovirus (n = 1) and Cyclovirus (n = 5), using a high-throughput-sequencing-based approach. Of these, the virus in the genus Circovirus represents a new species, as it shares only 54-60% genome-wide sequence identity with the other members of this genus. The five viruses in the genus Cyclovirus represent three new species, sharing <73% genome-wide sequence identity with all other cycloviruses. Three of the cycloviruses belong to a single putative species and were obtained from the feces of three individual bobcats, sharing 95.7-99.9% sequence identity, whereas the other two unique cycloviruses were identified in a single fecal sample. At present, it is unknown whether the identified viruses infect bobcats, their prey, or their gut parasites.

Novel polyomaviruses identified in fecal samples from four carnivore species.

Polyomaviruses are oncogenic viruses that are generally thought to have co-evolved with their hosts. While primate and rodent polyomaviruses are increasingly well-studied, less is known about polyomaviruses that infect other mammals. In an effort to gain insight into polyomaviruses associated with carnivores, we surveyed fecal samples collected in the USA from bobcats (Lynx rufus), pumas (Puma concolor), Canada lynxes (Lynx canadensis), and grizzly bears (Ursus arctos). Using a viral metagenomic approach, we identified six novel polyomavirus genomes. Surprisingly, four of the six genomes showed a phylogenetic relationship to polyomaviruses found in prey animals. These included a putative rabbit polyomavirus from a bobcat fecal sample and two possible deer-trophic polyomaviruses from Canada lynx feces. One polyomavirus found in a grizzly bear sample was found to be phylogenetically distant from previously identified polyomaviruses. Further analysis of the grizzly bear fecal sample showed that it contained anelloviruses that are known to infect pigs, suggesting that the bear might have preyed on a wild or domestic pig. Interestingly, a polyomavirus genome identified in a puma fecal sample was found to be closely related both to raccoon polyomavirus 1 and to Lyon-IARC polyomavirus, the latter of which was originally identified in human saliva and skin swab specimens but has since been found in samples from domestic cats (Felis catus).

Genomic analyses of gray fox lineages suggest ancient divergence and secondary contact in the southern Great Plains.

The gray fox (Urocyon cinereoargenteus) lineage diverged from all other extant canids at their most basal node and is restricted to the Americas. Previous mitochondrial analysis from coastal populations identified deeply divergent (up to 1 Mya) eastern and western lineages that predate most intraspecific splits in carnivores. We conducted genotyping by sequencing and mitochondrial analysis on gray foxes sampled across North America to determine geographic concordance between nuclear and mitochondrial contact zones and divergence times. We also estimated the admixture within the contact zone between eastern and western gray foxes based on nuclear DNA. Both datasets confirmed that eastern and western lineages met in the southern Great Plains (i.e. Texas and Oklahoma), where they maintained high differentiation. Admixture was generally low, with the majority of admixed individuals carrying <10% ancestry from the other lineage. Divergence times confirmed a mid-Pleistocene split, similar to the mitochondrial estimates. Taken together, findings suggest gray fox lineages represent an ancient divergence event, far older than most intraspecific divergences in North American carnivores. Low admixture may reflect a relatively recent time since secondary contact (e.g. post-Pleistocene) or, alternatively, ecological or reproductive barriers between lineages. Though further research is needed to disentangle these factors, our genomic investigation suggests species-level divergence exists between eastern and western gray fox lineages.

The Effects of Safe Zone Badges in Physicians' Online Biographies: Evidence from an Experimental Study.

Earning digital badges to showcase a person's expertise or knowledge are becoming increasingly popular. A healthcare provider's displaying of a Safe Zone badge within their online profile may offer prospective patients a cue as to the kind of care they might receive if they selected that particular provider. Prior research indicates LGBTQ+ individuals are looking for these types of cues within providers' biographies to make their selections. A between subjects, 2 (Safe Zone badge present/absent) x 2 (male/female doctor) online experiment was conducted (n = 658). Results revealed a main effect for the presence of the Safe Zone badge. Participants had greater anticipated satisfaction, liking, were more likely to view the provider as approachable, and were more willing to schedule an appointment with the provider displaying a Safe Zone badge.

Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final Report.

PURPOSE: Our goal was to evaluate long-term safety and durability of response to UGN-101, a mitomycin-containing reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma. MATERIALS AND METHODS: In this open-label, single-arm, multicenter, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term followup; 23/41 patients (56%) remained in complete response after 12 months (95% CI 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs. CONCLUSIONS: Durability of response to UGN-101 with or without maintenance treatment is clinically meaningful, offering a kidney-sparing therapeutic alternative for patients with low-grade disease.

Drug instillation in the management of urinary tract urothelial carcinoma.

PURPOSE OF REVIEW: This article aimed to investigate the efficacy of drug instillation therapy in preventing the recurrence of postsurgical upper urinary tract urothelial carcinoma (UTUC) by reviewing recently published research articles. RECENT FINDINGS: Several clinical trials have shown new potential forms of postsurgical intracavitary and intravesical drug instillation methodologies with better efficacy and less toxicity for use in UTUC. With the improvement of endoscopic imaging techniques and laser sciences, diverse attempts in drug instillation have shown an improved recurrence rate after kidney-sparing surgery in low-grade, low-tumor burden cancers in the upper urinary tract. A gel-form type of mitomycin-C in intracavitary instillation further reduced recurrence rates in UTUC. Other studies have compared different drug instillation methodologies with varying initiation times and timed instillation. They have shown that early instillation with multiple rounds resulted in better protective effects for recurrence rates before, during, and after surgery. SUMMARY: A new gel-form of intracavitary instillation of mitomycin-C, the timing of drug instillation, and refining techniques can result in better recurrence-free survival of patients with UTUC after surgery. Further large-scale prospective clinical trials are needed to validate these new forms of drugs and methodologies to change the therapeutic guidelines of UTUC.

Targeting FGFR3 alterations with adjuvant infigratinib in invasive urothelial carcinoma: the phase III PROOF 302 trial.

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1-21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics.

Cancers of the bladder and other parts in the urinary system, especially those that are invasive and grow into the muscle layer, may need extra treatment after surgical removal of the tumor, particularly if there is a high risk of the cancer coming back. Chemotherapy regimens that include cisplatin are often used postoperatively, although some patients are unable to tolerate this treatment or refuse it. FGFR3, a protein that is encoded by the FGFR3 gene, is often changed in these cancers. This helps the tumor grow. Infigratinib is an investigational drug that targets FGFR3 and inhibits the abnormal growth of the tumor. In the PROOF 302 study, patients are randomly assigned to treatment with infigratinib or a placebo pill for 1 year after surgery to see if the drug is effective. The aim is to see if patients who take infigratinib have a longer time free from the disease than those who receive a placebo. The study will also look at how long patients remain free from cancer spread and how long they live overall. The study will also investigate how safe the treatment is and how easy it is to live with it. PROOF 302 is an important study as it will define the role of infigratinib in patients with cancers of the bladder and urinary system who also have FGFR3 changes, for whom more treatment choices are needed. Clinical Trial Registration: NCT04197986 (ClinicalTrials.gov).

When Doctors Swear, Do Patients Care? Two Experiments Examining Physicians Cursing in the Presence of Patients.

Swearing in everyday conversation has become more normalized in recent years; but less certain, however, is how accepting Americans are when a doctor swears in their presence. Two online experiments (Study 1: n = 497; Study 2: n = 1,224) were conducted with US participants to investigate the impact of a doctor swearing in the course of examining a patient's infected wound (i.e., "You've got a lot of nasty [shit/stuff] in there that we're going to want to flush out"), or swearing when dropping papers in a patient's presence while varying the intensity of a swear (i.e., "[Shit!/Damn!/Whoops!]"), with or without an apology (i.e., "I'm sorry"). Overall findings reveal a main effect for swearing, with a swearing doctor generally seen as less likable, and in Study 1, less trustworthy, approachable, and less of an expert. However, the majority of participants exposed to a swearing doctor still said they would visit that physician again. Open-ended responses from these participants revealed that they perceived a swearing doctor as more human. Results from Study 2 also found that if a doctor swore, the negative impact was lessened if the doctor apologized immediately after cursing. While results from these studies indicate it is wise for doctors to refrain from swearing, most participants were still willing to make a future appointment with a cursing doctor.

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.

The influence of species life history and distribution characteristics on species responses to habitat fragmentation in an urban landscape.

Fragmentation within urbanized environments often leads to a loss of native species diversity; however, variation exists in responses among-species and among-populations within species. We aimed to identify patterns in species biogeography in an urbanized landscape to understand anthropogenic effects on vertebrate communities and identify species that are more sensitive or resilient to landscape change. We investigated patterns in species richness and species responses to fragmentation in southern Californian small vertebrate communities using multispecies occupancy models and determined factors associated with overall commonness and sensitivity to patch size for 45 small vertebrate species both among and within remaining non-developed patches. In general, smaller patches had fewer species, with amphibian species richness being particularly sensitive to patch size effects. Mammals were generally more common, occurring both in a greater proportion of patches and a higher proportion of the sites within occupied patches. Alternatively, amphibians were generally restricted to larger patches but were more ubiquitous within smaller patches when occupied. Species range size was positively correlated with how common a species was across and within patches, even when controlling for only patches that fell within a species' range. We found sensitivity to patch size was greater for more fecund species and depended on where the patch occurred within a species' range. While all taxa were more likely to occur in patches in the warmer portions of their ranges, amphibians and mammals were more sensitive to fragmentation in these warmer areas as compared to the rest of their ranges. Similarly, amphibians occurred at a smaller proportion of sites within patches in drier portions of their ranges. Mammals occurred at a higher proportion of sites that were also in drier portions of their range while reptiles did not differ in their sensitivity to patch size by range position. We demonstrate that taxonomy, life history, range size and range position can predict commonness and sensitivity of species across this highly fragmented yet biodiverse landscape. The impacts of fragmentation on species communities within an urban landscape depend on scale, with differences emerging among and within species and populations.

Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance.

Cytotoxic chemotherapy is effective in debulking tumour masses initially; however, in some patients tumours become progressively unresponsive after multiple treatment cycles. Previous studies have demonstrated that cancer stem cells (CSCs) are selectively enriched after chemotherapy through enhanced survival. Here we reveal a new mechanism by which bladder CSCs actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles, using human bladder cancer xenografts. Further analyses demonstrate the recruitment of a quiescent label-retaining pool of CSCs into cell division in response to chemotherapy-induced damages, similar to mobilization of normal stem cells during wound repair. While chemotherapy effectively induces apoptosis, associated prostaglandin E2 (PGE2) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE2-neutralizing antibody and celecoxib drug-mediated blockade of PGE2 signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE2- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograft tumours, including primary xenografts derived from a patient who was resistant to chemotherapy. Collectively, these findings uncover a new underlying mechanism that models the progressive development of clinical chemoresistance, and implicate an adjunctive therapy to enhance chemotherapeutic response of bladder urothelial carcinomas by abrogating early tumour repopulation.

The state of health communication research: A content analysis of articles published in Journal of Health Communication and Health Communication (2010-2019).

This study presents data from a content analysis of original research articles published in Journal of Health Communication (JOHC) andHealth Communication (HC) from 2010 to 2019. The authors coded 2,050 articles using categories that identified health topics, theory, population characteristics, and methods used in each study. Distinctions between the published research in JOHCand HCare highlighted. Across both journals, articles are primarily conducted within the United States, most frequently use college student samples, often lack explicit theoretical frameworks, heavily rely on online survey methods, and most commonly use quantitative methodologies. The most frequently utilized theory across both journals wasSocial Cognitive Theory and the most studied health topic were behaviors related to smoking, tobacco, and e-cigarette use. The journals were significantly different in several areas, with HC containing more articles explicitly guided by theory and publishing more qualitative research, while JOHC had more racial diversity in its study samples. Results are discussed in terms of their implications for future research. Increased diversity in methodology and samples, as well as increased use of theory and continued use of interdisciplinary collaborations among researchers will allow for expanding and enhancing health communication knowledge going forward.