Personalized cancer therapy is based on a patient’s tumor lineage, histopathology, expression analyses, and/or tumor DNA or RNA analysis. Here, we aim to develop an in vitro functional assay of a ...patient’s living cancer cells that could complement these approaches. We present methods for developing cell cultures from tumor biopsies and identify the types of samples and culture conditions associated with higher efficiency of model establishment. Toward the application of patient-derived cell cultures for personalized care, we established an immunofluorescence-based functional assay that quantifies cancer cell responses to targeted therapy in mixed cell cultures. Assaying patient-derived lung cancer cultures with this method showed promise in modeling patient response for diagnostic use. This platform should allow for the development of co-clinical trial studies to prospectively test the value of drug profiling on tumor-biopsy-derived cultures to direct patient care.
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•Successful culture of cancer cells from tumor biopsies•An immunofluorescence-based assay to quantify drug sensitivity in mixed cell cultures•NSCLC patients’ biopsy culture sensitivities reflect clinical response
Kodack et al. report on the development of cancer models from tumor biopsies and technologies toward a functional approach for personalized medicine. They describe the ability to reliably test drug response in patient-derived samples of mixed cell populations. In doing so, they show that patient biopsy cultures may predict patient clinical responses.
Understanding how human activities influence immune response to environmental stressors can support biodiversity conservation across increasingly urbanizing landscapes. We studied a bobcat (Lynx ...rufus) population in urban southern California that experienced a rapid population decline from 2002–2005 due to notoedric mange. Because anticoagulant rodenticide (AR) exposure was an underlying complication in mange deaths, we aimed to understand sublethal contributions of urbanization and ARs on 65 biochemical markers of immune and organ function. Variance in immunological variables was primarily associated with AR exposure and secondarily with urbanization. Use of urban habitat and AR exposure has pervasive, complex and predictable effects on biochemical markers of immune and organ function in free-ranging bobcats that include impacts on neutrophil, lymphocyte and cytokine populations, total bilirubin and phosphorus. We find evidence of both inflammatory response and immune suppression associated with urban land use and rat poison exposure that could influence susceptibility to opportunistic infections. Consequently, AR exposure may influence mortality and has population-level effects, as previous work in the focal population has revealed substantial mortality caused by mange infection. The secondary effects of anticoagulant exposure may be a worldwide, largely unrecognized problem affecting a variety of vertebrate species in human-dominated environments.
Abstract There is limited information regarding the effectiveness of probiotic feed additives in the diet of lactating dairy cows. This study aimed to determine the effect that Fastrack probiotic had ...on the yield and milk quality measures of lactating dairy cows. To accomplish this goal, lactating Holstein cows (n = 80) were equally divided into two treatment groups: one supplemented with a probiotic (PRO) and one that did not receive the probiotic supplement (CON). The cows remained in their treatment groups for the duration of the 120-d study and were given ad libitum access to a total mixed ration consisting of 35% corn silage, 30% rolled corn, 10.5% soybean meal, 23% DDGS, and 1.5% mineral supplement. Cows on the PRO treatment were given 1 kg of DDGS once a day at milking that had the probiotic mixed in while the CON treatment were given 1 kg of the same DDGS that did not have the probiotic included. Preliminary results of this study show a decrease in individual treatment records for cows on the PRO treatment and an increase of 2 kg of milk yield per day.
Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational ...changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.
Severe mental illness (SMI; schizophrenia, bipolar disorders (BDs), and other nonorganic psychoses) is associated with increased risk of cardiovascular disease (CVD) and CVD-related mortality. To ...date, no systematic review has investigated changes in population level CVD-related mortality over calendar time. It is unclear if this relationship has changed over time in higher-income countries with changing treatments.
To address this gap, a systematic review was conducted, to assess the association between SMI and CVD including temporal change. Seven databases were searched (last: November 30, 2021) for cohort or case-control studies lasting ≥1 year, comparing frequency of CVD mortality or incidence in high-income countries between people with versus without SMI. No language restrictions were applied. Random effects meta-analyses were conducted to compute pooled hazard ratios (HRs) and rate ratios, pooled standardised mortality ratios (SMRs), pooled odds ratios (ORs), and pooled risk ratios (RRs) of CVD in those with versus without SMI. Temporal trends were explored by decade. Subgroup analyses by age, sex, setting, world region, and study quality (Newcastle-Ottawa scale (NOS) score) were conducted. The narrative synthesis included 108 studies, and the quantitative synthesis 59 mortality studies (with (≥1,841,356 cases and 29,321,409 controls) and 28 incidence studies (≥401,909 cases and 14,372,146 controls). The risk of CVD-related mortality for people with SMI was higher than controls across most comparisons, except for total CVD-related mortality for BD and cerebrovascular accident (CVA) for mixed SMI. Estimated risks were larger for schizophrenia than BD. Pooled results ranged from SMR = 1.55 (95% confidence interval (CI): 1.33 to 1.81, p < 0.001), for CVA in people with BD to HR/rate ratio = 2.40 (95% CI: 2.25 to 2.55, p < 0.001) for CVA in schizophrenia. For schizophrenia and BD, SMRs and pooled HRs/rate ratios for CHD and CVD mortality were larger in studies with outcomes occurring during the 1990s and 2000s than earlier decades (1980s: SMR = 1.14, 95% CI: 0.57 to 2.30, p = 0.71; 2000s: SMR = 2.59, 95% CI: 1.93 to 3.47, p < 0.001 for schizophrenia and CHD) and in studies including people with younger age. The incidence of CVA, CVD events, and heart failure in SMI was higher than controls. Estimated risks for schizophrenia ranged from HR/rate ratio 1.25 (95% CI: 1.04 to 1.51, p = 0.016) for total CVD events to rate ratio 3.82 (95% CI: 3.1 to 4.71, p < 0.001) for heart failure. Incidence of CHD was higher in BD versus controls. However, for schizophrenia, CHD was elevated in higher-quality studies only. The HR/rate ratios for CVA and CHD were larger in studies with outcomes occurring after the 1990s. Study limitations include the high risk of bias of some studies as they drew a comparison cohort from general population rates and the fact that it was difficult to exclude studies that had overlapping populations, although attempts were made to minimise this.
In this study, we found that SMI was associated with an approximate doubling in the rate ratio of CVD-related mortality, particularly since the 1990s, and in younger groups. SMI was also associated with increased incidence of CVA and CHD relative to control participants since the 1990s. More research is needed to clarify the association between SMI and CHD and ways to mitigate this risk.
The Developing Inclusive Youth program is a classroom‐based, individually administered video tool that depicts peer‐based social and racial exclusion, combined with teacher‐led discussions. A ...multisite randomized control trial was implemented with 983 participants (502 females; 58.5% White, 41.5% Ethnic/racial minority; Mage = 9.64 years) in 48 third‐, fourth‐, and fifth‐grade classrooms across six schools. Children in the program were more likely to view interracial and same‐race peer exclusion as wrong, associate positive traits with peers of different racial, ethnic, and gender backgrounds, and report play with peers from diverse backgrounds than were children in the control group. Many approaches are necessary to achieve antiracism in schools. This intervention is one component of this goal for developmental science.
In response to some resource inequalities, children give priority to moral concerns. Yet, in others, children show ingroup preferences in their evaluations and resource allocations. The present study ...built upon this knowledge by investigating children's and young adults’ (N = 144; 5–6‐year‐olds, Mage = 5.83, SDage = .97; 9–11‐year‐olds, Mage = 10.74, SDage = .68; and young adults, Mage = 19.92, SDage = 1.10) evaluations and allocation decisions in a science inequality context. Participants viewed vignettes in which male and female groups received unequal amounts of science supplies, then evaluated the acceptability of the resource inequalities, allocated new boxes of science supplies between the groups, and provided justifications for their choices. Results revealed both children and young adults evaluated inequalities of science resources less negatively when girls were disadvantaged than when boys were disadvantaged. Further, 5‐ to 6‐year‐old participants and male participants rectified science resource inequalities to a greater extent when the inequality disadvantaged boys compared to when it disadvantaged girls. Generally, participants who used moral reasoning to justify their responses negatively evaluated and rectified the resource inequalities, whereas participants who used group‐focused reasoning positively evaluated and perpetuated the inequalities, though some age and participant gender findings emerged. Together, these findings reveal subtle gender biases that may contribute to perpetuating gender‐based science inequalities both in childhood and adulthood.
We present a cohort of 41 patients with osimertinib resistance biopsies, including 2 with an acquired
fusion. Although
fusions have been identified in resistant
-mutant non-small cell lung cancer ...(NSCLC), their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of
fusions in an
-mutant cancer, we expressed CCDC6-RET in PC9 (
del19) and MGH134 (
L858R/T790M) cells and found that CCDC6-RET was sufficient to confer resistance to EGFR tyrosine kinase inhibitors (TKI). The selective RET inhibitors BLU-667 and cabozantinib resensitized CCDC6-RET-expressing cells to EGFR inhibition. Finally, we treated 2 patients with
-mutant NSCLC and
-mediated resistance with osimertinib and BLU-667. The combination was well tolerated and led to rapid radiographic response in both patients. This study provides proof of concept that
fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective treatment strategy for such patients. SIGNIFICANCE: The role of
fusions in resistant
-mutant cancers is unknown. We report that
fusions mediate resistance to EGFR inhibitors and demonstrate that this bypass track can be effectively targeted with a selective RET inhibitor (BLU-667) in the clinic.
.
(
), a Gram-positive bacterium, is responsible for causing a wide variety of invasive infections. The emergence of multi-drug antibiotic resistance has prompted the search for antimicrobial ...alternatives. Phage-derived peptidoglycan hydrolases, known as endolysins, are an attractive alternative. In this study, an endolysin active against
, designated SP-CHAP, was cloned, produced, purified, biochemically characterized, and evaluated for its antimicrobial properties. Cysteine, histidine-dependent amidohydrolase/peptidase (CHAP) domains are widely represented in bacteriophage endolysins but have never previously been reported for pneumococcal endolysins. Here, we characterize the first pneumococcal endolysin with a CHAP catalytic domain. SP-CHAP was antimicrobial against all
serovars tested, including capsular and capsule-free pneumococci, and it was found to be more active than the most widely studied pneumococcal endolysin, Cpl-1, while not affecting various oral or nasal commensal organisms tested. SP-CHAP was also effective in eradicating
biofilms at concentrations as low as 1.56 µg/mL. In addition, a
mouse nasopharyngeal colonization model was employed, which showed that SP-CHAP caused a significant reduction in
colony-forming units, even more than Cpl-1. These results indicate that SP-CHAP may represent a promising alternative to combating
infections.
Considering the high rates of pneumococcal resistance reported for several antibiotics, alternatives are urgently needed. In the present study, we report a
-targeting endolysin with even greater activity than Cpl-1, the most characterized pneumococcal endolysin to date. We have employed a combination of biochemical and microbiological assays to assess the stability and lytic potential of SP-CHAP and demonstrate its efficacy on pneumococcal biofilms
and in an
mouse model of colonization. Our findings highlight the therapeutic potential of SP-CHAP as an antibiotic alternative to treat
infections.
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