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In recent years, microRNAs (miRNAs or miRs) have been increasingly studied for their role in cancer and have shown potential as cancer biomarkers. miR‑143‑3p and miR‑143‑5p are the mature miRNAs derived from pre‑miRNA‑143. At present, there are numerous studies on the function of miR‑143‑3p in cancer progression, but there are no systematic reviews describing the function of miR‑143‑3p in cancer. It is widely considered that miR‑143‑3p is downregulated in most malignant tumors and that upstream regulators can act on this gene, which in turn regulates the corresponding target to act on the tumor. In addition, miRNA‑143‑3p can regulate target genes to affect the biological process of tumors through various signaling pathways, such as the PI3K/Akt, Wnt/β‑catenin, AKT/STAT3 and Ras‑Raf‑MEK‑ERK pathways. The present review comprehensively described the biogenesis of miR‑143‑3p, the biological functions of miR‑143‑3p and the related roles and mechanisms in different cancer types. The potential of miR‑143‑3p as a biomarker for cancer was also highlighted and valuable future research directions were discussed.

Purpose: Invasive candidiasis poses a life-threatening risk, and early prognosis assessment is vital for timely interventions to reduce mortality. Serum C5a levels have recently been linked to prognosis, but confirmation in cancer patients is pending., Methods: We detected the concentrations of serum C5a in hospitalized cancer patients with invasive candidiasis from 2020 to 2023, and retrospectively analyzed the clinical data., Results: 372 cases were included in this study, with a 90-day mortality rate of 21.8%. Candida albicans (48.7%) remained the predominant pathogen, followed by Candida glabrata (25.5%), Candida tropicalis (12.4%), and Candida parapsilosis (8.3%). Gastrointestinal cancer was the most diagnosed pathology type (37.6%). Serum C5a demonstrated a noteworthy correlation with 90-day mortality, and employing a cutoff value of 36.7 ng/ml revealed significantly higher 90-day mortality in low-C5a patients (41.2%) compared to high-C5a patients (6.3%) (p < 0.001). We also identified no source control, no surgery, metastasis, or chronic renal failure independently correlated with the 90-day mortality. Based on this, a prognostic model combining C5a and clinical parameters was constructed, which performed better than models built solely on C5a or clinical parameters. Furthermore, we weighted scores to each parameter in the model and presented diagnostic sensitivity and specificity corresponding to different score points calculated by the model., Conclusion: We constructed a prognostic scoring model including serum C5a and clinical parameters, which would contribute to precise prognosis assessment and benefit the outcome among cancer patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The N6-methyladenosine (M6A) modification is the most common internal chemical modification of RNA molecules in eukaryotes. This modification can affect mRNA metabolism, regulate RNA transcription, nuclear export, splicing, degradation, and translation, and significantly impact various aspects of physiology and pathobiology. Radiotherapy is the most common method of tumor treatment. Different intrinsic cellular mechanisms affect the response of cells to ionizing radiation (IR) and the effectiveness of cancer radiotherapy. In this review, we summarize and discuss recent advances in understanding the roles and mechanisms of RNA M6A methylation in cellular responses to radiation-induced DNA damage and in determining the outcomes of cancer radiotherapy. Insights into RNA M6A methylation in radiation biology may facilitate the improvement of therapeutic strategies for cancer radiotherapy and radioprotection of normal tissues.

In contemporary oncology, radiation therapy and immunotherapy stand as critical treatments, each with distinct mechanisms and outcomes. Radiation therapy, a key player in cancer management, targets cancer cells by damaging their DNA with ionizing radiation. Its effectiveness is heightened when used alongside other treatments like surgery and chemotherapy. Employing varied radiation types like X-rays, gamma rays, and proton beams, this approach aims to minimize damage to healthy tissue. However, it is not without risks, including potential damage to surrounding normal cells and side effects ranging from skin inflammation to serious long-term complications. Conversely, immunotherapy marks a revolutionary step in cancer treatment, leveraging the body's immune system to target and destroy cancer cells. It manipulates the immune system's specificity and memory, offering a versatile approach either alone or in combination with other treatments. Immunotherapy is known for its targeted action, long-lasting responses, and fewer side effects compared to traditional therapies. The interaction between radiation therapy and immunotherapy is intricate, with potential for both synergistic and antagonistic effects. Their combined use can be more effective than either treatment alone, but careful consideration of timing and sequence is essential. This review explores the impact of various radiation therapy regimens on immunotherapy, focusing on changes in the immune microenvironment, immune protein expression, and epigenetic factors, emphasizing the need for personalized treatment strategies and ongoing research to enhance the efficacy of these combined therapies in cancer care., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Followed by Candida albicans, Candida glabrata ranks as the second major species contributing to invasive candidiasis. Given the higher medical burden and lower susceptibility to azoles in C. glabrata infections, identifying these infections is critical. From 2016 to 2021, patients with deep-seated candidiasis due to C. glabrata and non-glabrata Candida met the criteria to be enrolled in the study. Clinical data were randomly divided into training and validation cohorts. A predictive model and nomogram were constructed using R software based on the stepwise algorithm and logistic regression. The performance of the model was assessed by the area under the receiver operating characteristic curve and decision curve analysis (DCA). A total of 197 patients were included in the study, 134 of them infected with non-glabrata Candida and 63 with C. glabrata. The predictive model for C. glabrata infection consisted of gastrointestinal cancer, co-infected with bacteria, diabetes mellitus, and kidney dysfunction. The specificity was 84.1% and the sensitivity was 61.5% in the validation cohort when the cutoff value was set to the same as the training cohort. Based on the model, treatment for patients with a high-risk threshold was better than 'treatment for all' in DCA, while opting low-risk patients out of treatment was also better than 'treatment for none' in opt-out DCA. The predictive model provides a rapid method for judging the probability of infections due to C. glabrata and will be of benefit to clinicians making decisions about therapy strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Recently, endoradiotherapy based on actinium-225 ( 225 Ac) has attracted increasing attention, which is due to its α particles can generate maximal damage to cancer cells while minimizing unnecessary radiation effects on healthy tissues. Herein, 111 In/ 225 Ac-radiolabeled conjugated polymer nanoparticles (CPNs) coated with amphiphilic polymer DSPE-PEG-DOTA have been developed as a new injectable nano-radiopharmaceuticals for cancer endoradiotherapy under the guidance of nuclear imaging. Single photon emission computed tomography/computed tomography (SPECT/CT) using 111 In-DOTA-PEG-CPNs as nano probe indicates a prolonged retention of radiolabeled nanocarriers, which was consistent with the in vivo biodistribution examined by direct radiometry analysis. Significant inhibition of tumor growth has been observed in murine 4T1 models treated with 225 Ac-DOTA-PEG-CPNs when compared to mice treated with PBS or DOTA-PEG-CPNs. The 225 Ac-DOTA-PEG-CPNs group experienced no single death within 24 days with the median survival considerably extended to 35 days, while all the mice treated with PBS or DOTA-PEG-CPNs died at 20 days post injection. Additionally, the histopathology studies demonstrated no obvious side effects on healthy tissues after treatment with 225 Ac-DOTA-PEG-CPNs. All these results reveal that the new 225 Ac-labeled DOTA-PEG-CPNs is promising as paradigm for endoradiotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chromatin remodeling and N 6 -methyladenosine (m 6 A) modification are two critical layers in controlling gene expression and DNA damage signaling in most eukaryotic bioprocesses. Here, we report that poly(ADP-ribose) polymerase 1 (PARP1) controls the chromatin accessibility of METTL3 to regulate its transcription and subsequent m 6 A methylation of poly(A) + RNA in response to DNA damage induced by radiation. The transcription factors nuclear factor I-C (NFIC) and TATA binding protein (TBP) are dependent on PARP1 to access the METTL3 promoter to activate METTL3 transcription. Upon irradiation or PARP1 inhibitor treatment, PARP1 disassociated from METTL3 promoter chromatin, which resulted in attenuated accessibility of NFIC and TBP and, consequently, suppressed METTL3 expression and RNA m 6 A methylation. Lysophosphatidic Acid Receptor 5 (LPAR5) mRNA was identified as a target of METTL3, and m 6 A methylation was located at A1881. The level of m 6 A methylation of LPAR5 significantly decreased, along with METTL3 depression, in cells after irradiation or PARP1 inhibition. Mutation of the LPAR5 A1881 locus in its 3' UTR results in loss of m 6 A methylation and, consequently, decreased stability of LPAR5 mRNA. METTL3-targeted small-molecule inhibitors depress murine xenograft tumor growth and exhibit a synergistic effect with radiotherapy in vivo. These findings advance our comprehensive understanding of PARP-related biological roles, which may have implications for developing valuable therapeutic strategies for PARP1 inhibitors in oncology., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Conformal sphincter preservation operation (CSPO) procedure is a sphincter preservation procedure for preserving the anal canal function for very low rectal cancers. This study investigated the functional and oncological outcome of conformal sphincter preservation operation by comparing with low anterior resection (LAR) and abdominoperineal resection (APR)., Methods: This is a retrospective comparative study. Patients who received conformal sphincter preservation operation (n = 52), low anterior resection (n = 54), or abdominoperineal resection (n = 69) were included between 2011 and 2016 in a tertiary referral hospital. Propensity score matching was applied to adjust the baseline characteristics which may influence the choice of the surgical procedure., Results: Twenty-one pairs of conformal sphincter preservation operation vs. low anterior resection and 29 pairs of conformal sphincter preservation operation vs. abdominoperineal resection were selected. The first group had a higher tumor location than the second group. Compared with the low anterior resection group, the conformal sphincter preservation operation group had shorter distal resection margins; however, no significant differences were identified in daily stool frequency, Wexner incontinence score, local recurrence, distant metastasis, overall survival, and disease-free survival between both groups. Compared with the abdominoperineal resection group, the conformal sphincter preservation operation group had shorter operative time and shorter postoperative hospital stay. No significant differences were identified in local recurrence, distant metastasis, overall survival, and disease-free survival., Conclusion: Conformal sphincter preservation operation is oncologically safe compared to APR and LAR, and has similar functional findings to LAR. Studies comparing CSPO with intersphincteric resection should be performed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors works by reactivating immune cells. Considering the accessibility of noninvasive liquid biopsies, it is advisable to employ peripheral blood lymphocyte subsets to predict immunotherapy outcomes., Methods: We retrospectively enrolled 87 patients with available baseline circulating lymphocyte subset data who received first-line PD-1/PD-L1 inhibitors at Peking Union Medical College Hospital between May 2018 and April 2022. Immune cell counts were determined by flow cytometry., Results: Patients who responded to PD-1/PD-L1 inhibitors had significantly higher circulating CD8+CD28+ T-cell counts (median [range] count: 236 [30-536] versus 138 [36-460]/μL, p < 0.001). Using 190/μL as the cutoff value, the sensitivity and specificity of CD8+CD28+ T cells for predicting immunotherapy response were 0.689 and 0.714, respectively. Furthermore, the median progression-free survival (PFS, not reached versus 8.7 months, p < 0.001) and overall survival (OS, not reached versus 16.2 months, p < 0.001) were significantly longer in the patients with higher CD8+CD28+ T-cell counts. However, the CD8+CD28+ T-cell level was also associated with the incidence of grade 3-4 immune-related adverse events (irAEs). The sensitivity and specificity of CD8+CD28+ T cells for predicting irAEs of grade 3-4 were 0.846 and 0.667, respectively, at the threshold of CD8+CD28+ T cells ≥ 309/μL., Conclusions: High circulating CD8+CD28+ T-cell levels is a potential biomarker for immunotherapy response and better prognosis, while excessive CD8+CD28+ T cells (≥ 309/μL) may also indicate the emergence of severe irAEs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Geng, Tang, You, Xu, Li, Li, Liu, Qiu, Zhou, Li, Ge, Guo, Sun, Wang, Li and Bai.)

The efficiency of reactive oxygen species (ROS)-based photodynamic therapy (PDT) is far from satisfactory, because cancer cells can adapt to PDT by upregulating glutathione (GSH) levels. The GSH levels in tumor cells are determined based on glutamine availability via alanine-serine-cysteine transporter 2 (ASCT2)-mediated entry into cells. Herein, we develop co-assembled nanoparticles (PPa/V-9302 NPs) of the photosensitizer pyropheophorbide a (PPa) and V-9302 (a known inhibitor of ASCT2) in a 1:1 M ratio using a one-step precipitation method to auto-enhance photodynamic therapy. The computational simulations revealed that PPa and V-9302 could self-assemble through different driving forces, such as π-π stacking, hydrophobic interactions, and ionic bonds. Such PPa/V-9302 NPs could disrupt the intracellular redox homeostasis due to enhanced ROS production via PPa-induced PDT and reduced GSH synthesis via inhibition of the ASCT2-mediated glutamine flux by V-9302. The in vivo assays reveal that PPa/V-9302 NPs could increase the drug accumulation in tumor sites and suppress tumor growth in BALB/c mice bearing mouse breast carcinoma (4 T1) tumor. Our findings provide a new paradigm for the rational design of the PDT-based combinational cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The development of RAF inhibitors targeting cancers with wild type RAF kinase and/or RAS mutation has been challenging due to the paradoxical activation of the RAS-RAF-MEK-ERK cascade following RAF inhibitor treatment. Herein is the discovery and optimization of a series of RAF inhibitors with a novel spiro structure. The most potent spiro molecule 9 showed excellent in vitro potency against b/c RAF enzymes and RAS mutant H358 cancer cells with minimal paradoxical RAF signaling activation. Compound 9 also exhibited good drug-like properties as demonstrated by in vitro cytochrome P450 (CYP), liver microsome stability (LMS) data and moderate oral pharmacokinetics (PK) profiles in rat and mouse., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

MicroRNAs (miRNAs) are noncoding RNAs with 18-26 nucleotides; they pair with target mRNAs to regulate gene expression and produce significant changes in various physiological and pathological processes. In recent years, the interaction between miRNAs and their target genes has become one of the mainstream directions for drug development. As a large-scale biological database that mainly provides miRNA-target interactions (MTIs) verified by biological experiments, miRTarBase has undergone five revisions and enhancements. The database has accumulated >2 200 449 verified MTIs from 13 389 manually curated articles and CLIP-seq data. An optimized scoring system is adopted to enhance this update's critical recognition of MTI-related articles and corresponding disease information. In addition, single-nucleotide polymorphisms and disease-related variants related to the binding efficiency of miRNA and target were characterized in miRNAs and gene 3' untranslated regions. miRNA expression profiles across extracellular vesicles, blood and different tissues, including exosomal miRNAs and tissue-specific miRNAs, were integrated to explore miRNA functions and biomarkers. For the user interface, we have classified attributes, including RNA expression, specific interaction, protein expression and biological function, for various validation experiments related to the role of miRNA. We also used seed sequence information to evaluate the binding sites of miRNA. In summary, these enhancements render miRTarBase as one of the most research-amicable MTI databases that contain comprehensive and experimentally verified annotations. The newly updated version of miRTarBase is now available at https://miRTarBase.cuhk.edu.cn/., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Purpose: Imatinib, a small-molecule tyrosine kinase inhibitor, has shown good clinical activity by inhibiting adenosine triphosphate (ATP) binding to the receptor. Unfortunately, majority of patients eventually develop drug resistance, which limits the long-term benefits of the tyrosine kinase inhibitors and poses a significant challenge in the clinical management of GIST. The aim of our study was to explore the feasibility of blocking KIT dimerisation upstream of the phosphorylation in imatinib-resistant GIST., Method: KITMAb was prepared using hybridoma technique. The biological function of KITMAb was examined in KIT-dimer-expressing cells constructed by transfecting with liposomes using enzyme linked immunosorbent assay (ELISA), immunohistochemistry, western blot, MTT, Annexin V/FITC, and flow cytometry assay, respectively., Results: KIT-dimer was expressed in 293 cells transfected with c-kit mutated-type pcDNA3.1. Treatment of KIT-dimer-expressing cells with the KITMAb significantly decreased the expression of both KIT-dimer and other phosphorylated proteins of KIT downstream signalling pathway. Furthermore, KITMAb slowed down cell growth and reduced the proportion of cells in the proliferative phase (S + G2-M). Finally, we also found that KITMAb treatment accelerated cell apoptosis. These results indicate that KITMAb strongly inhibits KIT receptor dimerisation-mediated signalling pathway and cell growth responses in vitro., Conclusions: We demonstrate c-kit mutation-driven KIT auto-dimerisation prior to tyrosine kinase phosphorylation as same as the procedure in ligand-dependent signalling pathway and describe a monoclonal antibody, KITMAb, with strong affinity to the dimerisation domain of KIT that blocks the important step in both the KIT signalling pathways. Further, the results suggest that treatment with KITMAb may be potentially therapeutic in imatinib-resistant GIST.

Background: Invasive candidiasis is the most common fungal disease among hospitalized patients and continues to be a major cause of mortality. Risk factors for mortality have been studied previously but rarely developed into a predictive nomogram, especially for cancer patients. We constructed a nomogram for mortality prediction based on a retrospective review of 10 years of data for cancer patients with invasive candidiasis., Methods: Clinical data for cancer patients with invasive candidiasis during the period of 2010-2019 were studied; the cases were randomly divided into training and validation cohorts. Variables in the training cohort were subjected to a predictive nomogram based on multivariate logistic regression analysis and a stepwise algorithm. We assessed the performance of the nomogram through the area under the receiver operating characteristic (ROC) curve (AUC) and decision curve analysis (DCA) in both the training and validation cohorts., Results: A total of 207 cases of invasive candidiasis were examined, and the crude 30-day mortality was 28.0%. Candida albicans (48.3%) was the predominant species responsible for infection, followed by the Candida glabrata complex (24.2%) and Candida tropicalis (10.1%). The training and validation cohorts contained 147 and 60 cases, respectively. The predictive nomogram consisted of bloodstream infections, intensive care unit (ICU) admitted > 3 days, no prior surgery, metastasis and no source control. The AUCs of the training and validation cohorts were 0.895 (95% confidence interval [CI], 0.846-0.945) and 0.862 (95% CI, 0.770-0.955), respectively. The net benefit of the model performed better than "treatment for all" in DCA and was also better for opting low-risk patients out of treatment than "treatment for none" in opt-out DCA., Conclusion: Cancer patients with invasive candidiasis exhibit high crude mortality. The predictive nomogram established in this study can provide a probability of mortality for a given patient, which will be beneficial for therapeutic strategies and outcome improvement.

Background: Patients with malignancy are vulnerable to influenza viruses and are at high risk of developing serious complications. However, few studies have investigated the impact of influenza infection among hospitalised patients with malignancy., Methods: Cancer-related hospitalisations were identified by using data from National Inpatient Sample in the USA between 2012 and 2014. We conducted a 1:1 propensity score matching analysis to compare the in-hospital outcomes between cancer patients with and without influenza. Multivariate logistic regression analyses were also performed to identify independent prognosis predictors of mortality., Results: We identified 13 186 849 weighted cancer-related hospitalisations during the study period, and 47 850 of them (0.36%) had a concomitant diagnosis of influenza. After propensity score matching, cancer patients with concomitant influenza had a higher mortality (5.4% vs 4.2%; OR, 1.30; 95% CI, 1.13 to 1.49; p<0.001), longer length of stay (6.3 days vs 5.6 days; p<0.001) but lower costs (US$14 605.9 vs US$14 625.5; p<0.001) in hospital than those without influenza. In addition, cancer patients with influenza had a higher incidence of complications, including pneumonia (18.4% vs 13.2%; OR, 1.49; 95% CI, 1.37 to 1.62; p<0.001), neutropenia (7.1% vs 3.4%; OR, 2.18; 95% CI, 1.91 to 2.50; p<0.001), sepsis (19.5% vs 9.3%; OR, 2.36; 95% CI, 2.16 to 2.58; p<0.001), dehydration (14.8% vs 8.8%; OR, 1.80; 95% CI, 1.65 to 1.97; p<0.001) and acute kidney injury (19.9% vs 17.6%; OR, 1.16; 95% CI, 1.08 to 1.25; p<0.001) than those without influenza. Older age, no insurance, more comorbidities, lung cancer and haematological malignancy were independently associated with higher mortality., Conclusion: Influenza is associated with worse in-hospital clinical outcomes among hospitalised patients with malignancy. Annual influenza vaccination and early initiation of antiviral therapy are recommended in this high-risk population., Competing Interests: Competing interests: None declared., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Nanocarrier systems play an important role in cancer immunotherapy. In this article, biotinylated CD20 and CD3 antibodies were conjugated onto the surface of streptavidin modified ultra-small Fe 3 O 4 nanoparticles via specific binding between streptavidin and biotin to construct a bi-specific nanoplatform (BSNP). The synthesized BSNP with 30 nm hydrodynamic size provides a better magnetic resonance imaging ability than the clinical Gd-chelated contrast agents (r 1 value is 5.27 mM -1 s -1 and 4.52 mM -1 s -1 for BSNP and Magnevist, respectively). This nanoplatform can target CD20-positive Raji cells and enhance the T cell mediated cell killing effect in vitro. Further, it can also inhibit tumor growth and prolong the survival time of non-Hodgkin's lymphoma (NHL) xenograft model in vivo. The probable mechanism is that while BSNP can directly induce the apoptosis of Raji cell via aggregation of CD20, T cells are recruited around tumor cells by the BSNP leading to T cell-mediated tumor cell lysis. In addition, the enhanced dual-modal MRI-fluorescence images can be acquired. In summary, the modular designed BSNP provides an efficient immune-related cancer theranostic strategy, which is of great potential as a simple and universal nanoplatform by combining different antibodies to enhance the cancer theranostic efficacy.

Cancer immunotherapy as a novel cancer therapeutic strategy has shown enormous promise. However, the immunosuppressive tumor microenvironment (ITM) is a primary obstacle. Tumor-associated macrophages (TAMs) as a major component of immune cells in a tumor microenvironment are generally polarized to the M2 phenotype that not only accelerates tumor growth but also influences the infiltration of lymphocytes and leads to immunosuppression. Thus, rebuilding ITM by re-educating TAMs and increasing infiltration of lymphocytes is a promising strategy. Herein, gadofullerene (GF-Ala) nanoparticles are demonstrated to reprogram TAMs to M1-like and increase the infiltration of cytotoxic T lymphocytes (CTLs), achieving effective inhibition of tumor growth. Notably, the modulation of ITM by GF-Ala promotes the anticancer efficacy of anti-PD-L1 immune checkpoint inhibitor, achieving superior synergistic treatment. Additionally, GF-Ala nanoparticles can be mostly excreted from the body and cause no obvious toxicity. Together, this study provides an effective immunomodulation strategy using gadofullerene nanoparticles by rebuilding ITM and synergizing immune checkpoint blockade therapy.

Background: Epigenetic alterations are involved in most cancers, but its application in cancer diagnosis is still limited. More practical and intuitive methods to detect the aberrant expressions from clinical samples using highly sensitive biomarkers are needed. In this study, we developed a novel approach in identifying, visualizing, and quantifying the biallelic and multiallelic expressions of an imprinted gene panel associated with cancer status. We evaluated the normal and aberrant expressions measured using the imprinted gene panel to formulate diagnostic models which could accurately distinguish the imprinting differences of normal and benign cases from cancerous tissues for each of the ten cancer types., Results: The Quantitative Chromogenic Imprinted Gene In Situ Hybridization (QCIGISH) method developed from a 1013-case study which provides a visual and quantitative analysis of non-coding RNA allelic expressions identified the guanine nucleotide-binding protein, alpha-stimulating complex locus (GNAS), growth factor receptor-bound protein (GRB10), and small nuclear ribonucleoprotein polypeptide N (SNRPN) out of five tested imprinted genes as efficient epigenetic biomarkers for the early-stage detection of ten cancer types. A binary algorithm developed for cancer diagnosis showed that elevated biallelic expression (BAE), multiallelic expression (MAE), and total expression (TE) measurements for the imprinted gene panel were associated with cell carcinogenesis, with the formulated diagnostic models achieving consistently high sensitivities (91-98%) and specificities (86-98%) across the different cancer types., Conclusions: The QCIGISH method provides an innovative way to visually assess and quantitatively analyze individual cells for cancer potential extending from hyperplasia and dysplasia until carcinoma in situ and invasion, which effectively supplements standard clinical cytologic and histopathologic diagnosis for early cancer detection. In addition, the diagnostic models developed from the BAE, MAE, and TE measurements of the imprinted gene panel GNAS, GRB10, and SNRPN could provide important predictive information which are useful in early-stage cancer detection and personalized cancer management.

Caspase-8, a well-characterized initiator of apoptosis, has also been found to play non-apoptotic roles in cells. In this study, we reveal that caspase-8 can induce cell death in a special way, which does not depend on activation of caspases and mitochondrial initiation. Instead, we prove that caspase-8 can cause lysosomal deacidification and thus lysosomal membrane permeabilization. V-ATPase is a multi-subunit proton pump that acidifies the lumen of lysosome. Our results demonstrate that caspase-8 can bind to the V 0 domain of lysosomal Vacuolar H + -ATPase (V-ATPase), but not the V 1 domain, to block the assembly of functional V-ATPase and alkalinize lysosomes. We further demonstrate that the C-terminal of caspase-8 is mainly responsible for the interaction with V-ATPase and can suffice to inhibit survival of cancer cells. Interestingly, regardless of the protein level, it is the expression rate of caspase-8 that is the major cause of cell death. Taken together, we identify a previously unrevealed caspase-8-mediated cell death pathway different form typical apoptosis, which could render caspase-8 a particular physiological function and may be potentially applied in treatments for apoptosis-resistant cancers., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Cancer cells often proliferate under hypoxia and reprogram their metabolism. However, how to find targets to effectively block the hypoxia-associated metabolic pathways remains unclear. Here, we developed a tool to conveniently calculate electrons dissipated in metabolic transformations. Based on the law of conservation of electrons in chemical reactions, we further built up an electron balance model for central carbon metabolism, and it can accurately outline metabolic plasticity under hypoxia. Our model specifies that glutamine metabolism reprogrammed for biosynthesis of lipid and/or proline actually acts as the alternative electron bin to enable electron transfer in proliferating cells under hypoxia. Inhibition of both proline biosynthesis and lipogenesis can synergistically suppress cancer cell growth under hypoxia and in vivo tumor onset. Therefore, our model helps to reveal combinations of potential targets to inhibit tumor growth by blocking hypoxia-rewired metabolism and provides a useful tool for future studies on cancer metabolism., (© 2020 Liu et al.)

Antibody-drug conjugates have elicited great interest recently as targeted chemotherapies for cancer. Recent preclinical and clinical data have continued to raise questions about optimizing the design of these complex therapeutics. Biochemical methods for site-specific antibody conjugation have been a design feature of recent clinical ADCs, and preclinical reports suggest that site-specifically conjugated ADCs generically offer improved therapeutic indices (i.e., the fold difference between efficacious and maximum tolerated doses). Here we present the results of a systematic preclinical comparison of ADCs embodying the DNA-alkylating linker-payload DGN549 generated with both heterogeneous lysine-directed and site-specific cysteine-directed conjugation chemistries. Importantly, the catabolites generated by each ADC are the same regardless of the conjugation format. In two different model systems evaluated, the site-specific ADC showed a therapeutic index benefit. However, the therapeutic index benefit is different in each case: both show evidence of improved tolerability, though with different magnitudes, and in one case significant efficacy improvement is also observed. These results support our contention that conjugation chemistry of ADCs is best evaluated in the context of a particular antibody, target, and linker-payload, and ideally across multiple disease models.

Medicine is the main means to reduce cancer mortality. However, some medicines face various risks during transportation and storage due to the particularity of medicines, which must be kept at a low temperature to ensure their quality. In this regard, it is of great significance to evaluate and select drug cold chain logistics suppliers from different perspectives to ensure the quality of medicines and reduce the risks of transportation and storage. To solve such a multiple criteria decision-making (MCDM) problem, this paper proposes an integrated model based on the combination of the SWARA (stepwise weight assessment ratio analysis) and CoCoSo (combined compromise solution) methods under the probabilistic linguistic environment. An adjustment coefficient is introduced to the SWARA method to derive criteria weights, and an improved CoCoSo method is proposed to determine the ranking of alternatives. The two methods are extended to the probabilistic linguistic environment to enhance the applicability of the two methods. A case study on the selection of drug cold chain logistics suppliers is presented to demonstrate the applicability of the proposed integrated MCDM model. The advantages of the proposed methods are highlighted through comparative analyses.

Although inhibiting EGFR-mediated signaling proved to be effective in treating certain types of cancers, a quickly evolved mechanism that either restores the EGFR signaling or activates an alternative pathway for driving the proliferation and survival of malignant cells limits the efficacy and utility of the approach via suppressing the EGFR functionality. Given the fact that overexpression of EGFR is commonly seen in many cancers, an EGFR-targeting antibody-drug conjugate (ADC) can selectively kill cancer cells independently of blocking EGFR-mediated signaling. Herein, we describe SHR-A1307, a novel anti-EGFR ADC, generated from an anti-EGFR antibody with prolonged half-life, and conjugated with a proprietary toxin payload that has increased index of EGFR targeting-dependent versus EGFR targeting-independent cytotoxicity. SHR-A1307 demonstrated strong and sustained antitumor activities in EGFR-positive tumors harboring different oncogenic mutations on EGFR, KRAS, or PIK3CA. Antitumor efficacy of SHR-A1307 correlated with EGFR expression levels in vitro and in vivo , regardless of the mutation status of EGFR signaling mediators and a resultant resistance to EGFR signaling inhibitors. Cynomolgus monkey toxicology study showed that SHR-A1307 is well tolerated with a wide therapeutic index. SHR-A1307 is a promising therapeutic option for EGFR-expressing cancers, including those resistant or refractory to the EGFR pathway inhibitors., (©2019 American Association for Cancer Research.)

Under hypoxia, most of glucose is converted to secretory lactate, which leads to the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid over-accumulating ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate, which is indispensable to glutamine-carbon metabolism under hypoxia. We found that glutamine nitrogen is necessary to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. Furthermore, we found that the specific metabolic pathway occurs in vivo and is required for tumor growth. The identified metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Therefore, our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism.

Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared with those of the cross-linker. Thus, the improved in vivo tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment. Mol Cancer Ther; 17(3); 650-60. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Candidemia is the worldwide life-threaten disease, especially in cancer patients. This study was aimed to identify and evaluate the risk factors of candidemia in cancer patients, which will prompt the improvement on current therapeutic strategies and prognosis., Methods: A retrospective, case-control study was conducted from inpatients of Tianjin Medical University Cancer Institute and Hospital, during 2006 to 2013. Analyses were performed between cancer patients with candidemia as study case, and patients with bacterial bloodstream infections as control. Each case was matched up with two controls, for gender and inpatient duration. Candida species, clinical characteristics, risk factors and outcomes were reviewed in details., Results: Total number of 80 cases and 160 controls were enrolled and analyzed in this study. Candida albicans was identified as the most prevalent species and account for 55.0% candidemia, followed by Candida parapsilosis complex (21.3%), Candida tropicalis (8.8%), Candida glabrata complex (7.5%), Candida lusitaniae (3.8%), and Candida famata (3.8%). The crude mortality at 30-days of candidemia was up to 30.0%, which is significantly higher than bacterial bloodstream infections (p = 0.006). Logistical analysis demonstrated that total parenteral nutrition >5 days (p = 0.036), urinary catheter >2 days (p = 0.001), distant organ metastasis of cancer (p = 0.002) and gastrointestinal cancer (p = 0.042) were the independent risk factors for candidemia., Conclusions: Candidemia showed significant higher mortality than bacterial bloodstream infections, C. albicans was cited as the primary pathogen. Total parenteral nutrition, urinary catheter, distant organ metastasis of cancer and gastrointestinal cancer are independent predictors for candidemia, this findings provides potential therapeutic targets for improving the outcome.

AmpC β-lactamase-producing Escherichia coli (AmpC-EC) is one of the main antimicrobial resistant pathogens in patients with cancer. A cohort study was performed to evaluate the risk factors, antibiotic therapy, and outcomes of AmpC-EC bacteraemia in hospitalized cancer patients from September 2012 through December 2015. Two hundred forty-eight cases of E. coli bacteraemia were documented in cancer patients, 51 (20.6%) were caused by AmpC-EC and 197 (79.4%) were caused with non-AmpC-EC. Prior exposure to cephalosporins (OR 2.786; 95% CI: 1.094-7.091; P=0.032), carbapenems (OR 2.296; 95% CI: 1.054-5.004; P=0.036), and invasive procedures (OR 4.237; 95% CI: 1.731-10.37; P=0.002) were identified as independent risk factors for AmpC-EC. The time to positivity (TTP) of patients with AmpC-EC bacteraemia tended to be significantly shorter than that of non-AmpC-EC (8.33±2.18h versus 9.48±3.82h; P=0.006), and had a higher 30-day mortality rate in AmpC-EC compared with non-AmpC-EC (25.5% versus 12.2%; P=0.018). Metastasis (OR=2.778, 95% CI: 1.078-7.162; P=0.034), the presence of septic shock (OR=4.983, 95% CI: 1.761-14.10; P=0.002), and organ failure (OR=24.51 95% CI: 9.884-60.81; P<0.001) were independently associated with the overall mortality. The mortality rate showed a gradual increase when appropriate antibiotic therapy (AAT) was delayed more than 48h as determined by the trend test (P<0.001). In conclusion, this study showed that prevalence of AmpC-EC was high in hospitalized cancer patients of our area. Thus, it is necessary to apply appropriate therapeutic approaches and improve outcomes based on the analysis of risk factors for the acquisition of AmpC-EC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Time to positivity (TTP) has been used in recent years as a simple and rapid method for the additional characterization of the degree of bacteremia. However, prognostic factors for TTP in cancer patients with bloodstream infections have rarely been studied. The aim of this study was to investigate the clinical factors for TTP involving various isolated organisms in cancer patients., Methods: We analyzed 386 episodes of bloodstream infections (BSIs) in patients with or without cancer during a 19 month period. Information on age, gender, tumor type, ICU stay, organisms, multidrug resistance (MDR), TTP and outcome was collected. Multivariate logistic regression analysis was performed., Results: The mean TTP of Enterobacteriaceae in patients with hepatocellular carcinoma, gastroenterological cancer, and lung cancer was shorter than in non-cancer patients (9.86 ± 3.22, 10.05 ± 3.47, 8.85 ± 2.78 vs 13.11 ± 5.37 h). The mean TTP of nonfermentative bacilli in patients with lung cancer (12.37 ± 5.96 h) and hematologic diseases (8.72 ± 4.21 h) was also shorter than in non-cancer patients (20.74 ± 2.46 h), and the mean TTP of Staphylococcus isolates was significantly different between non-cancer patients (22.06 ± 3.71 h) and hematologic disease patients (11.93 ± 5.44 h). The presence of a benign tumor was a significant prognostic factor for a long TTP only in the Staphylococci group (OR 0.076, 95 % CI 0.014-0.412), according to multivariate analysis. MDR (OR 2.178, 95 % CI 1.196-4.239) was an independent significant predictor in the Enterobacteriaceae group, with a short TTP, and it was also a significant clinical factor for a long TTP in nonfermentative bacilli and the Staphylococci group (OR 5.037, 95 % CI 1.065-23.82; OR 0.167, 95 % CI 0.059-0.474)., Conclusion: Time to positivity provides useful diagnostic and prognostic information for the differentiation of frequently isolated organisms. This information may help clinicians to use the correct antibiotics in a timely manner to treat cancer patients with BSIs based on clinical factor analysis.

Antibody-drug conjugates (ADCs) are of great interest as targeted cancer therapeutics. Preparation of ADCs for early stage screening is constrained by purification and biochemical analysis techniques that necessitate burdensome quantities of antibody. Here we describe a method, developed for the maytansinoid class of ADCs, enabling parallel conjugation of antibodies in 96-well format. The method utilizes ∼ 100 µg of antibody per well and requires <5 µg of ADC for characterization. We demonstrate the capabilities of this system using model antibodies. We also provide multiple examples applying this method to early-stage screening of maytansinoid ADCs. The method can greatly increase the throughput with which candidate ADCs can be screened in cell-based assays, and may be more generally applicable to high-throughput preparation and screening of different types of protein conjugates.

In this study, we further investigated a previously developed aptamer targeting ROS 17/2.8 (rat osteosarcoma) cells. We found that this C6-8 aptamer specifically binds to heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 and that it specifically labeled multiple tumor-cell lines as effectively as hnRNP A2/B1 monoclonal antibodies. When conjugated with fluorescent carbon nanodots (CDots) it could freely enter multiple living tumor cell lines (HepG2, MCF-7, H1299, and HeLa), whose growth it inhibited by targeting hnRNP A2/B1. Similar inhibitory effects were observed when the GFP-HepG2 hepatocarcinoma cells treated with C6-8-conjugated CDots were implanted in nude mice. Our work provides a new aptamer for targeting/labeling multiple tumor cell types, and its nanoparticle conjugates bring further advantages that increase its potential for use in cancer diagnosis and therapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To determine the value of differential time to positivity (DTTP) of blood culture for the diagnosis of catheter-related bloodstream infection (CRBSI) in patients with solid tumors in intensive care unit (ICU)., Methods: A retrospective study was conducted. 615 pairs of peripheral vein blood cultures and instantaneous catheter tip blood culture of 615 patients admitted to ICU of Tianjin Medical University Cancer Institute and Hospital were collected from August 2011 to March 2014. The DTTP method and (or) semi quantitative culture of catheter tip were compared. CRBSI was diagnosed when both cultures were positive for the same microorganism and DTTP≥2 hours (120 minutes). The result of this procedure was compared with that of organism obtained using the semi quantitative culture of blood at catheter tip with ≥15 cfu. Based on the clinical diagnosis, the reliability of two kinds of laboratory examination was compared for the diagnosis of CRBSI by plotting receiver operator characteristic curve (ROC curve)., Results: The result of 615 cases suspected of having CRBSI were analyzed during the study period. Of these, 440 episodes were excluded because cultures were negative for blood obtained through peripheral vein and central vein. Eight episodes were excluded because only peripheral vein blood culture was positive and 57 episodes were excluded because of only central vein blood culture was positive, 68 pairs of blood cultures were excluded due to the presence of multiple catheters and repeated blood withdrawals. Two cases of polymicrobial cultures were excluded from the final analysis due to the difficulty in determining the time of positive result for each individual microorganism. Ten cases in 42 cases of suspected cases of CRBSI were excluded from analysis because catheter was not removed, therefore culture from catheter tip could not be obtained. Using the DTTP method, 14 out of 17 CRBSI cases were diagnosed with DTTP≥120 minutes, while 3 cases were missed; the semi quantitative catheter tip culture was positive in 13 cases, and in 4 cases it was neglected. In 2 cases of CRBSI it was missed by both methods. The area under the ROC curve (AUC) of DTTP, catheter tip culture and the combination method was 0.912, 0.882 and 0.941 for diagnosis of CRBSI, respectively. Validity values for the diagnosis of CRBSI for DTTP were: sensitivity 82.35%, specificity 92.31%, positive predictive value 93.33% and negative predictive value 80.00%, and they were higher than those of the catheter tip culture method only (76.47%, 84.62%, 86.67% and 73.33%). The specificity and positive predictive CRBSI combination of the two methods in the diagnosis value were up to 100%, the sensitivity (88.24%) and negative predictive value (86.67%) was also increased, but no significant differences were found with DTTP method (χ2=0.00, P=1.00; χ2=0.00, P=0.98; χ2=0.00, P=0.98; χ2=0.00, P=0.98)., Conclusions: DTTP can be a valid method recommended for CRBSI diagnosis in critically ill patients with acceptable sensitivity, good specificity as well as positive predictive value. DTTP combined with other clinical symptoms can not only avoid unnecessary catheter withdrawal, but it also can help obtain the optimal treatment time and strategy.

Background: Since the high morbidity and mortality of candidemia among cancer patients, the epidemiology has been underlined. In recent years, Candida species genotyping has been established, which could provide detail characteristics of epidemiology and has been underscored for candidemia preventing strategies., Methods: Data of cancer patients with candidemia and hospitalized in Tianjin Medical University Cancer Institute and Hospital (TMUCIH) during 2009-2013 were reviewed. Species identification was carried out by using VITEK-2 Compact. Microsatellite typing was performed for molecular analysis. SPSS 20.0 and MVSP 3.22 software were used for statistical and clustering analysis, respectively., Results: Total of 36 isolates of Candida albicans were recovered from 36 cancer patients with nosocomial candidemia in TMUCIH during the period of 2009-2013 included in the study. Total of 17 genotypes were identified and 2 of them were endemic genotypes, which caused 21 (58.3%) of 36 episodes of candidemia. Hepatobiliary oncology, ICU and gastrointestinal oncology were the main wards of infections due to endemic strains. Gastrointestinal cancer and insertion of a nasogastric tube were the predictors of infections caused by endemic strains (p = 0.014 and p = 0.041, respectively). For the 36 cases, crude mortality was up to 30.6%, and there was no significant difference between infections due to endemic and non-endemic strains (p = 0.077)., Conclusions: This study proved that endemic stains of C. albicans could exist for a long period and mainly in a few wards. Patients with gastrointestinal cancer or nasogastric tube insertion were more sensitive to endemic C. albicans., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: China is experiencing a rapid increase in cancer incidence in elderly patients. In order to better understand this group, a large study of patients from multiple tertiary centers in the Beijing area was designed. This study was designed to provide insight into their unique treatment preferences, including the use of traditional Chinese medicine (TCM)., Materials and Methods: 803 patients from nine hospitals in the Beijing area were enrolled into this study. The inclusion criteria were patients who were 65 years or older and had a diagnosis of cancer at any stage. The CGA questionnaire used with these patients included the Chinese translation of the Gero-Oncology Health and Quality of Life Assessment tool. The questionnaire was provided to patients by a research nurse and was administered in Mandarin., Results: The mean age of the patients was 72 years (range 65-94). The patients were mainly male (59.8%) and of Han ethnicity (95.4%). About 45% of these patients also had concurrent TCM in addition to their other cancer treatments. About 70% were able to manage their activities of daily living without assistance. Patients on TCM were more likely to have higher number of co-morbidities compared to their counterparts., Conclusion: This is the largest prospective study of CGA assessments done on elderly patients with cancer in Asia. The study demonstrates that CGA provides insights into understanding the needs of elderly Chinese patients with cancer. TCM is used frequently in China, and its impact on quality of life needs further investigation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Lymphocytes play important roles in the balance between body defense and noxious agents involved in a number of diseases, e.g. autoimmune diseases, allergic inflammation and cancer. The proteomic analyses have been applied to identify and validate disease-associated and disease-specific biomarkers for therapeutic strategies of diseases. The proteomic profiles of lymphocytes may provide more information to understand their functions and roles in the development of diseases, although proteomic approaches in lymphocytes are still limited. The present review overviewed the proteomics-based studies on lymphocytes to headlight the proteomic profiles of lymphocytes in diseases, such as autoimmune diseases, allergic inflammation and cancer, with a special focus on lung diseases. We will explore the potential significance of diagnostic biomarkers and therapeutic targets from the current status in proteomic studies of lymphocytes and discuss the value of the currently available proteomic methodologies in the lymphocytes research.

Expanded activated autologous lymphocyte (EAAL) therapy with CD3(+)CD8(+) cytotoxic T lymphocyte and CD3(-)56(+) natural killer cell as the major effector cells is a type of adoptive cell therapy. In this study, 19 patients with metastatic tumors received EAAL therapy. Two to four weeks after the administration of EAAL cells, the subsets of CD3(+)CD8(+) T lymphocytes and CD3(-)CD56(+) natural killer cells in the peripheral blood were increased significantly in comparison with those before the therapy. The number of IFN-γ secreting cells also significantly increased after the EAAL infusion (p=0.002) and the p values for the counts of CD3(+)IFN-γ(+) lymphocytes and CD3(-)IFN-γ(+) lymphocytes were 0.006 and 0.015, respectively. Moreover, the percentage of IFN-γ producing cells of the CD3(+), CD8(+) and CD3(-) subsets after infusion were all increased significantly, which indicated that EAAL therapy was able to enrich the potentially anti-tumor cytotoxic peripheral blood lymphocytes., (Copyright © 2010. Published by Elsevier Inc.)

Epithelial cells play an important role in physiological and pathophysiological situations, with organ-, tissue-, type-, and function-specific patterns. Proteome analysis has been used to study epithelial-origin diseases and identify novel prognostic, diagnostic, and therapeutic markers. The present review compares the variation of sample preparation for epithelial proteomic analysis, search similarities, and differences of epithelial proteomics between different cells, locations, and diseases. We focus on specificity of proteomic markers for epithelial-involved diseases. Proteomic alterations in epithelial cell lines were mapped to understand protein patterns, differentiation, oncogenesis, and pathogenesis of epithelial-origin diseases. Changes of proteomic patterns depend on different epithelial cell lines, challenges, and preparation. Epithelial protein profiles associated with intracellular locations and protein function. Epithelial proteomics has been greatly developed to link clinical questions, e.g., disease severity, biomarkers for disease diagnosis, and drug targets. There is an exciting and attractive start to link epithelial proteomics with histology of clinical samples. From the present review, we can find that most of disease-associated investigation of epithelial proteomics has been focused on epithelial-origin cancer. There is a significant gap of epithelial proteomics between acute and chronic organ injury, inflammation, and multiple organ dysfunction. Epithelial proteomics will provide powerful information on the relationships between biological molecules and disease mechanisms. Epithelial proteomics strategies and approaches should become more global, multidimensional, and systemic.

Unlabelled: There has been considerable debate about the desirability of attenuation correction in whole-body PET oncology imaging. The advantages of attenuation correction are quantitative accuracy, whereas the perceived disadvantages are loss of contrast, noise amplification, and increased scanning time. In this work, we explain contrast changes between images reconstructed with and without attenuation correction., Methods: To analytically explain both well-known and surprising phenomena in images reconstructed without attenuation correction, we performed a series of simulation studies, a phantom experiment, and a patient experiment., Results: We showed that it is possible to calculate a priori the appearance of images reconstructed without attenuation correction. Compared with attenuation-corrected images, images without attenuation correction may have locally enhanced contrast in the abdomen or other regions of uniform attenuation, although the amount of enhancement varies with position in a complex manner. In regions of nonuniform attenuation, such as the thorax, it is possible that foci of increased tracer uptake disappear in images reconstructed without attenuation correction. The critical tracer concentration for this zero-contrast effect depends on the size, location, and density of the foci. Above the critical value, foci are visible in images with and without attenuation correction, whereas below the critical value, foci are visible in attenuation-corrected images but appear as photopenic regions in images without attenuation correction., Conclusion: Even though images without attenuation correction may be desired, these results suggest that all studies should at least be reconstructed with attenuation correction to avoid missing regions of elevated tracer uptake.