Head-to-head comparison of 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT in the evaluation of primary digestive system cancer: a systematic review and meta-analysis

IntroductionAlthoug 18F-FDG positron emission tomography/computed tomography (PET/CT) is widely accepted as a diagnostic tool for detecting digestive cancers, 68Ga-FAPI-04 PET/CT may perform better in detecting gastrointestinal malignancies at an earlier stage. This study aimed to systematically review the diagnostic performance of 68Ga-FAPI-04 PET/CT compared with that of 18F-FDG PET/CT in primary digestive system cancers.MethodsIn this study, a comprehensive search using the PubMed, EMBASE, and Web of Science databases was performed to identify studies that met the eligibility criteria from the beginning of the databases to March 2023. The quality of the relevant studies with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) method was assessed using the RevMan 5.3 software. Sensitivity and specificity were calculated using bivariate random-effects models, and heterogeneity was assessed with the I2 statistic and meta-regression analysis using the R 4.22 software.ResultsA total of 800 publications were identified in the initial search. Finally, 15 studies comprising 383 patients were included in the analysis. The pooled sensitivity and specificity of 68Ga-FAPI-04 PET/CT were 0.98 (95% CI, 0.94–1.00) and 0.81 (95% CI, 0.23–1.00), whereas those of 18F-FDG PET/CT were 0.73 (95% CI, 0.60–0.84) and 0.77 (95% CI, 0.52–0.95), respectively. 68Ga-FAPI-04 PET/CT performed better for specific tumours, particularly in gastric, liver, biliary tract, and pancreatic cancers. Both imaging modalities had essentially the same diagnostic efficacy in colorectal cancer.Conclusions68Ga-FAPI-04 PET/CT showed a higher diagnostic ability than 18F-FDG PET/CT in terms of diagnosing primary digestive tract cancers, especially gastric, liver, biliary tract, and pancreatic cancers. The certainty of the evidence was high due to the moderately low risk of bias and low concern regarding applicability. However, the sample size of the included studies was small and heterogeneous. More high-quality prospective studies are needed to obtain higher-quality evidence in the future.Systematic Review RegistrationThe systematic review was registered in PROSPERO [CRD42023402892]

Examining resilience in local adaptation policies – pilot studies in Taipei and Tainan, Taiwan

Resilience has gained considerable attention over recent years in both theories and decision-making practices. In Taiwan, the term resilience is generally considered as a synonym for adaptation. This may limit the use of the notion. By understanding resilience in terms of adaptation and mitigation, we identify six attributes for assessment. The assessment is addressed in local level climate change adaptation policies in two selected cities. The city of Taipei represents places where local adaptation policies were directed mainly by the national government. The city of Tainan represents places where the municipal government plays a more critical role in framing these policies. This can result in different policymaking considerations. The assessment points out that the proposed actions of these policies are broader than a general understanding of adaptation. Mitigation strategies are addressed and sometimes highly recommended. Because of this, we can interpret these actions as resilience strategies covered under the use of the term adaptation. The notion of resilience does not stay on the rhetorical level alone. It is happening in shaping decisions – without using the terminology directly. The broadness of the resilience notion, in spite of being abstract, can provide a more general framework for cross-sectorial discussion and collaboration in policy-making. This is particularly important for dealing with complex issues, such as climate-related disturbances, which cannot be managed by a single group of professions

Case report: Intraabdominal infection of Mycobacterium syngnathidarum in an immunocompetent patient confirmed by whole-genome sequencing

BackgroundThe taxonomic group of non-tuberculous mycobacteria (NTM) encompasses more than 190 species and subspecies, some of which can cause pulmonary and extrapulmonary diseases across various age groups in humans. However, different subspecies exhibit differential drug sensitivities, and traditional detection techniques struggle to accurately classify NTM. Therefore, clinicians need more effective detection methods to identify NTM subtypes, thus providing personalized medication for patients.Case presentationWe present the case of a 47-year-old female patient diagnosed with an intraabdominal infection caused by Mycobacterium syngnathidarum. Despite computed tomography of the chest suggesting potential tuberculosis, tuberculosis infection was ruled out due to negative TB-DNA results for ascites fluid and sputum and limited improvement of lung lesions after treatment. Additionally, acid-fast staining and Lowenstein–Jensen culture results revealed the presence of mycobacterium in ascites fluid. Subsequent whole-genome sequencing (WGS) confirmed the DNA sequences of Mycobacterium syngnathidarum in colonies isolated from the ascites fluid, which was further corroborated by polymerase chain reaction and Sanger sequencing. Ultimately, the patient achieved a complete recovery following the treatment regimen targeting Mycobacterium syngnathidarum, which involved clarithromycin, ethambutol hydrochloride, pyrazinamide, rifampicin, and isoniazid.ConclusionThis is the first reported case of Mycobacterium syngnathidarum infection in humans. Mycobacterium syngnathidarum was detected by WGS in this case, suggesting that WGS may serve as a high-resolution assay for the diagnosis of different subtypes of mycobacterium infection

Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

Severe acute respiratory syndrome–coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus’s inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)–mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds

Tracking smell loss to identify healthcare workers with SARS-CoV-2 infection

Introduction Healthcare workers (HCW) treating COVID-19 patients are at high risk for infection and may also spread infection through their contact with vulnerable patients. Smell loss has been associated with SARS-CoV-2 infection, but it is unknown whether monitoring for smell loss can be used to identify asymptomatic infection among high risk individuals. In this study we sought to determine if tracking smell sensitivity and loss using an at-home assessment could identify SARS-CoV-2 infection in HCW. Methods and findings We performed a prospective cohort study tracking 473 HCW across three months to determine if smell loss could predict SARS-CoV-2 infection in this high-risk group. HCW subjects completed a longitudinal, behavioral at-home assessment of olfaction with household items, as well as detailed symptom surveys that included a parosmia screening questionnaire, and real-time quantitative polymerase chain reaction testing to identify SARS-CoV-2 infection. Our main measures were the prevalence of smell loss in SARS-CoV-2-positive HCW versus SARS-CoV- 2-negative HCW, and timing of smell loss relative to SARS-CoV-2 test positivity. SARS-CoV-2 was identified in 17 (3.6%) of 473 HCW. HCW with SARS-CoV-2 infection were more likely to report smell loss than SARS-CoV-2-negative HCW on both the at-home assessment and the screening questionnaire (9/17, 53% vs 105/456, 23%, P < .01). 6/9 (67%) of SARS-CoV-2-positive HCW reporting smell loss reported smell loss prior to having a positive SARS-CoV-2 test, and smell loss was reported a median of two days before testing positive. Neurological symptoms were reported more frequently among SARS-CoV-2-positive HCW who reported smell loss compared to those without smell loss (9/9, 100% vs 3/8, 38%, P < .01). Conclusions In this prospective study of HCW, self-reported changes in smell using two different measures were predictive of SARS-CoV-2 infection. Smell loss frequently preceded a positive test and was associated with neurological symptoms

Characterization of Human DNA Polymerase Delta and Its Subassemblies Reconstituted by Expression in the Multibac System

Mammalian DNA polymerase δ (Pol δ), a four-subunit enzyme, plays a crucial and versatile role in DNA replication and DNA repair processes. We have reconstituted human Pol δ complexes in insect cells infected with a single baculovirus into which one or more subunits were assembled. This system allowed for the efficient expression of the tetrameric Pol δ holoenzyme, the p125/p50 core dimer, the core+p68 trimer and the core+p12 trimer, as well as the p125 catalytic subunit. These were isolated in milligram amounts with reproducible purity and specific activities by a highly standardized protocol. We have systematically compared their activities in order to gain insights into the roles of the p12 and p68 subunits, as well as their responses to PCNA. The relative specific activities (apparent kcat) of the Pol δ holoenzyme, core+p68, core+p12 and p125/p50 core were 100, 109, 40, and 29. The corresponding apparent Kd's for PCNA were 7.1, 8.7, 9.3 and 73 nM. Our results support the hypothesis that Pol δ interacts with PCNA through multiple interactions, and that there may be a redundancy in binding interactions that may permit Pol δ to adopt flexible configurations with PCNA. The abilities of the Pol δ complexes to fully extend singly primed M13 DNA were examined. All the subassemblies except the core+p68 were defective in their abilities to completely extend the primer, showing that the p68 subunit has an important function in synthesis of long stretches of DNA in this assay. The core+p68 trimer could be reconstituted by addition of p12

Single cell atlas for 11 non-model mammals, reptiles and birds.

The availability of viral entry factors is a prerequisite for the cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Large-scale single-cell screening of animal cells could reveal the expression patterns of viral entry genes in different hosts. However, such exploration for SARS-CoV-2 remains limited. Here, we perform single-nucleus RNA sequencing for 11 non-model species, including pets (cat, dog, hamster, and lizard), livestock (goat and rabbit), poultry (duck and pigeon), and wildlife (pangolin, tiger, and deer), and investigated the co-expression of ACE2 and TMPRSS2. Furthermore, cross-species analysis of the lung cell atlas of the studied mammals, reptiles, and birds reveals core developmental programs, critical connectomes, and conserved regulatory circuits among these evolutionarily distant species. Overall, our work provides a compendium of gene expression profiles for non-model animals, which could be employed to identify potential SARS-CoV-2 target cells and putative zoonotic reservoirs

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival