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In vivo, the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM. Unbiased omics studies revealed the novel molecular mechanism of PIM's antitumor activity, which included suppression of the ATR/CDK2/E2F axis, MYC, and AuroraA/B signaling. Interestingly, the genes upregulated by PIM were largely associated with cholesterol homeostasis, which may contribute to PIM's side effects and should be given more attention. Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma.After chemotherapy, fewer than 30% of patients with T-cell lymphoma (T-NHL) are long-term disease-free survivors. Thus, there is a growing interest in allogeneic stem cell transplantation (alloSCT) and its potential graft-versus-lymphoma effect (GVL) for patient with high-risk or recurrent T-NHL with the aim at providing durable disease control in T-NHL. We conducted this registry study to evaluate the outcome of recipients of alternative donor alloSCT for T-NHL. Patients transplanted with Haploidentical donor (Haplo, n = 41) or Umbilical Cord Blood (UCB, n = 54) were analyzed for overall survival (OS), non-relapse mortality (NRM), relapse, and acute/chronic graft-versus-host disease (aGVHD/cGVHD) incidence. At 2 years, OS and PFS were, respectively, of 59% and 53%, without significant difference between Haplo and UCB. In multivariate analysis, disease status at transplant was an independent risk factor for OS and PFS, and aGVHD III-IV was the main factor for OS and NRM. While no major impact of donor source on survival and mortality was noted, this study suggests that alternative donor transplantation appears feasible and offers benefits to patients with T-cell lymphoma.Undefined starter cultures are poorly characterized bacterial communities from environmental origin used in cheese making. They are phenotypically stable and have evolved through domestication by repeated propagation in closed and highly controlled environments over centuries. This makes them interesting for understanding eco-evolutionary dynamics governing microbial communities. While cheese starter cultures are known to be dominated by a few bacterial species, little is known about the composition, functional relevance, and temporal dynamics of strain-level diversity. Here, we applied shotgun metagenomics to an important Swiss cheese starter culture and analyzed historical and experimental samples reflecting 82 years of starter culture propagation. We found that the bacterial community is highly stable and dominated by only a few coexisting strains of Streptococcus thermophilus and Lactobacillus delbrueckii subsp. lactis. Genome sequencing, metabolomics analysis, and co-culturing experiments of 43 isolates show that these strains are functionally redundant, but differ tremendously in their phage resistance potential. Moreover, we identified two highly abundant Streptococcus phages that seem to stably coexist in the community without any negative impact on bacterial growth or strain persistence, and despite the presence of a large and diverse repertoire of matching CRISPR spacers. Our findings show that functionally equivalent strains can coexist in domesticated microbial communities and highlight an important role of bacteria-phage interactions that are different from kill-the-winner dynamics.The symbiont "Candidatus Aquarickettsia rohweri" infects a diversity of aquatic hosts. In the threatened Caribbean coral, Acropora cervicornis, Aquarickettsia proliferates in response to increased nutrient exposure, resulting in suppressed growth and increased disease susceptibility and mortality of coral. This study evaluated the extent, as well as the ecology and evolution of Aquarickettsia infecting threatened corals, Ac. cervicornis, and Ac. palmata and their hybrid ("Ac. prolifera"). Aquarickettsia was found in all acroporids, with coral host and geographic location impacting the infection magnitude. Phylogenomic and genome-wide single-nucleotide variant analysis of Aquarickettsia found phylogenetic clustering by geographic region, not by coral taxon. Analysis of Aquarickettsia fixation indices suggests multiple sequential infections of the same coral colony are unlikely. Furthermore, relative to other Rickettsiales species, Aquarickettsia is undergoing positive selection, with Florida populations experiencing greater positive selection relative to other Caribbean locations. This may be due in part to Aquarickettsia proliferating in response to greater nutrient stress in Florida, as indicated by greater in situ replication rates in these corals. Aquarickettsia was not found to significantly codiversify with either the coral animal or the coral's algal symbiont (Symbiodinium "fitti"). Quantitative PCR analysis showed that gametes, larvae, recruits, and juveniles from susceptible, captive-reared coral genets were not infected with Aquarickettsia. Thus, horizontal transmission of Aquarickettsia via coral mucocytes or an unidentified host is more likely. The prevalence of Aquarickettsia in Ac. cervicornis and its high abundance in the Florida coral population suggests that coral disease mitigation efforts focus on preventing early infection via horizontal transmission.Over the last few years, the complexity and diversity of gut microbiota within and across individuals has been detailed in relation to human health. Further, understanding of the bidirectional association between gut microbiota and metabolic disorders has highlighted a complimentary, yet crucial role for microbiota in the onset and progression of obesity-related cancers. While strategies for cancer prevention and cure are known to work efficiently when supported by healthy diet and lifestyle choices and physical activity, emerging evidence suggests that the complex interplay relating microbiota both to neoplastic and metabolic diseases could aid strategies for cancer treatment and outcomes. This review will explore the experimental and clinical grounds supporting the functional role of gut microbiota in the pathophysiology and progression of cancers in relation to obesity and its metabolic correlates. Therapeutic approaches aiding microbiota restoration in connection with cancer treatments will be discussed.
Decision-making deficits in obesity and alcohol use disorder (AUD) may contribute to the choice of immediate rewards despite their long-term deleterious consequences.

Gambling task functional MRI in Human connectome project (HCP) dataset was used to investigate neural activation differences associated with reward or punishment (a key component of decision-making behavior) in 418 individuals with obesity (high BMI) and without obesity (lean BMI) and either at high (HR) or low (LR) risk of AUD based on their alcohol drinking levels.

Interaction between BMI and alcohol drinking was seen in regions of the default mode network (DMN) and those implicated in self-related processing, memory, and salience attribution. ObesityHR relative to obesityLR also recruited DMN along with primary motor and regions implicated in inattention, negative perception, and uncertain choices, which might facilitate impulsive choices in obesityHR. read more Furthermore, obesityHR compared to leanHR/leanLR also demonstrated heightened activatstive of worse executive function from excessive alcohol use. Delayed discounting measures failed to distinguish between obesity and high alcohol drinking levels, which as for gambling task results suggests independent negative effects of obesity and chronic alcohol drinking on decision-making. These findings highlight distinct associations of obesity and high-risk alcohol drinking with two key constituents of decision-making behavior.Although panoramic radiography has a role in the examination of patients with cleft alveolus (CA), its appearances is sometimes difficult to interpret. The aims of this study were to develop a computer-aided diagnosis system for diagnosing the CA status on panoramic radiographs using a deep learning object detection technique with and without normal data in the learning process, to verify its performance in comparison to human observers, and to clarify some characteristic appearances probably related to the performance. The panoramic radiographs of 383 CA patients with cleft palate (CA with CP) or without cleft palate (CA only) and 210 patients without CA (normal) were used to create two models on the DetectNet. The models 1 and 2 were developed based on the data without and with normal subjects, respectively, to detect the CAs and classify them into with or without CP. The model 2 reduced the false positive rate (1/30) compared to the model 1 (12/30). The overall accuracy of Model 2 was higher than Model 1 and human observers. The model created in this study appeared to have the potential to detect and classify CAs on panoramic radiographs, and might be useful to assist the human observers.Two challenges that the global wheat industry is facing are a lowering nitrogen-use efficiency (NUE) and an increase in the reporting of wheat-protein related health issues. Sulphur deficiencies in soil has also been reported as a global issue. The current study used large-scale field and glasshouse experiments to investigate the sulphur fertilization impacts on sulphur deficient soil. Here we show that sulphur addition increased NUE by more than 20% through regulating glutamine synthetase. Alleviating the soil sulphur deficiency highly significantly reduced the amount of gliadin proteins indicating that soil sulphur levels may be related to the biosynthesis of proteins involved in wheat-induced human pathologies. The sulphur-dependent wheat gluten biosynthesis network was studied using transcriptome analysis and amino acid metabolomic pathway studies. The study concluded that sulphur deficiency in modern farming systems is not only having a profound negative impact on productivity but is also impacting on population health.Screening for therapeutic targets is standard of care in the management of advanced non-small cell lung cancer. However, most molecular assays utilize tumor tissue, which may not always be available. "Liquid biopsies" are plasma-based next generation sequencing (NGS) assays that use circulating tumor DNA to identify relevant targets. To compare the sensitivity, specificity, and accuracy of a plasma-based NGS assay to solid-tumor-based NGS we retrospectively analyzed sequencing results of 100 sequential patients with lung adenocarcinoma at our institution who had received concurrent testing with both a solid-tissue-based NGS assay and a commercially available plasma-based NGS assay. Patients represented both new diagnoses (79%) and disease progression on treatment (21%); the majority (83%) had stage IV disease. Tissue-NGS identified 74 clinically relevant mutations, including 52 therapeutic targets, a sensitivity of 94.8%, while plasma-NGS identified 41 clinically relevant mutations, a sensitivity of 52.6% (p  less then  0.001). Tissue-NGS showed significantly higher sensitivity and accuracy across multiple patient subgroups, both in newly diagnosed and treated patients, as well as in metastatic and nonmetastatic disease. Discrepant cases involved hotspot mutations and actionable fusions including those in EGFR, ALK, and NTRK1. In summary, tissue-NGS detects significantly more clinically relevant alterations and therapeutic targets compared to plasma-NGS, suggesting that tissue-NGS should be the preferred method for molecular testing of lung adenocarcinoma when tissue is available. Plasma-NGS can still play an important role when tissue testing is not possible. However, given its low sensitivity, a negative result should be confirmed with a tissue-based assay.
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