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Introduction: Synthetic lethality (SL) provides an opportunity to leverage different genetic interactions when designing synergistic combination therapies. To further explore SL-based combination therapies for cancer treatment, it is important to identify and mechanistically characterize more SL interactions. Artificial intelligence (AI) methods have recently been proposed for SL prediction, but the results of these models are often not interpretable such that deriving the underlying mechanism can be challenging., Objectives: This study aims to develop an interpretable AI framework for SL prediction and subsequently utilize it to design SL-based synergistic combination therapies., Methods: We propose a knowledge and data dual-driven AI framework for SL prediction (KDDSL). Specifically, we use gene knowledge related to the SL mechanism to guide the construction of the model and develop a method to identify the most relevant gene knowledge for the predicted results., Results: Experimental and literature-based validation confirmed a good balance between predictive and interpretable ability when using KDDSL. Moreover, we demonstrated that KDDSL could help to discover promising drug combinations and clarify associated biological processes, such as the combination of MDM2 and CDK9 inhibitors, which exhibited significant anti-cancer effects in vitro and in vivo., Conclusion: These data underscore the potential of KDDSL to guide SL-based combination therapy design. There is a need for biomedicine-focused AI strategies to combine rational biological knowledge with developed models., 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 © 2024. Production and hosting by Elsevier B.V.)

Dual-attribute immune cells possess advantageous features of cytotoxic T cells and natural killer (NK) cells and hold promise for advancing immunotherapy. Dual-attribute cell types such as invariant natural killer T cells, induced T-to-NK cells, and cytokine-induced killer cells have demonstrated efficacy and safety in preclinical and clinical studies. However, their limited availability hinders their widespread application. Human pluripotent stem cells (hPSCs) offer an ideal source. Here, we generate dual-attribute induced T-NK (iTNK) cells from hPSCs, expressing markers of both cytotoxic T and NK cells. Single-cell RNA and T cell receptor (TCR) sequencing analyses reveal that iTNK cells expressed signature genes associated with both NK and T cells and displayed a diverse TCR repertoire. iTNK cells release cytotoxic mediators, exert cytotoxicity against diverse tumor cell lines, and inhibit tumor growth in vivo. By harnessing adaptive and innate immune responses, hPSC-derived iTNK cells offer promising strategies for cancer immunotherapy., Competing Interests: Declaration of interests H.D., Y.Z., and C.W. have a patent application related to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Adolescents and young adults (ie, individuals aged 15-39 years, known as AYAs) with cancer face unique vulnerabilities yet remain underrepresented in clinical trials, including adult registries of COVID-19 in cancer (AYAs: 8%-12%). We used the Pediatric Oncology COVID-19 Case Report to examine the clinical course of COVID-19 among AYAs with cancer. The Pediatric Oncology COVID-19 Case Report collects deidentified clinical and sociodemographic data regarding individuals aged from birth to 39 years with cancer (37%) and COVID-19 from more than 100 institutions. Between April 1, 2020, and November 28, 2023, 191 older AYAs (individuals 22-39 years of age) and 640 younger AYAs (individuals 15-21 years of age) were captured. Older AYAs were less often hospitalized (P < .001), admitted to the intensive care unit (P = .02), and required respiratory support (P = .057). In multivariable analyses, older AYAs faced 80% lower odds of intensive care unit admission but 2.3-times greater odds of changes to cancer-directed therapy. Unvaccinated patients had 5.4-times higher odds of intensive care unit admission. Among AYAs with cancer, the COVID-19 course varies by age. These findings can inform oncology teams directing COVID-19 management and prevention in AYA patients with cancer., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Photodynamic therapy (PDT) efficacy of bismuth sulfide (Bi 2 S 3 ) semiconductor has been severely restricted by its electron-hole pairs (e - -h + ) separation inefficiency and oxygen (O 2 ) deficiency in tumors, which greatly hinders reactive oxygen species (ROS) generation and further clinical application of Bi 2 S 3 nanoparticles (NPs) in biomedicine., Results: Herein, novel Bi 2 S 3 /titanium carbide (Ti 3 C 2 ) two-dimensional nano-heterostructures (NHs) are designed to realize multimode PDT of synchronous O 2 self-supply and ROS generation combined with highly efficient photothermal tumor elimination for hypoxic tumor therapy. Bi 2 S 3 /Ti 3 C 2 NHs were synthesized via the in situ synthesis method starting from Ti 3 C 2 nanosheets (NSs), a classical type of MXene nanostructure. Compared to simple Bi 2 S 3 NPs, Bi 2 S 3 /Ti 3 C 2 NHs significantly extend the absorption to the near-infrared (NIR) region and enhance the photocatalytic activity owing to the improved photogenerated carrier separation, where the hole on the valence band (VB) of Bi 2 S 3 can react with water to supply O 2 for the electron on the Ti 3 C 2 NSs to generate ·O 2 - and ·OH through electron transfer. Furthermore, they also achieve 1 O 2 generation through energy transfer due to O 2 self-supply. After the modification of triphenylphosphium bromide (TPP) on Bi 2 S 3 C 3 C 2 NHs, systematic in vitro and in vivo evaluations were conducted, revealing that the synergistic-therapeutic outcome of this nanoplatform enables complete eradication of the U251 tumors without recurrence by NIR laser irradiation, and it can be used for computed tomography (CT) imaging because of the strong X-ray attenuation ability., Conclusion: This work expands the phototherapeutic effect of Bi 2 S 3 -based nanoplatforms, providing a new strategy for hypoxic tumor theranostics., (© 2024. The Author(s).)

Lysine-specific demethylase 1 (LSD1) is a promising therapeutic target, especially in cancer treatment. Despite several LSD1 inhibitors being discovered for the cofactor pocket, none are FDA-approved. We aimed to develop stabilized peptides for irreversible LSD1 binding, focusing on unique cysteine residue Cys360 in LSD1 and SNAIL1. We created LSD1 C360-targeting peptides, like cyclic peptide S9-CMC1, using our Cysteine-Methionine cyclization strategy. S9-CMC1 effectively inhibited LSD1 at the protein level, as confirmed by MS analysis showing covalent bonding to Cys360. In cells, S9-CMC1 inhibited LSD1 activity, increasing H3K4me1 and H3K4me2 levels, leading to G1 cell cycle arrest and apoptosis and inhibiting cell proliferation. Remarkably, S9-CMC1 showed therapeutic potential in A549 xenograft animal models, regulating LSD1 activity and significantly inhibiting tumor growth with minimal organ damage. These findings suggest LSD1 C360 as a promising site for covalent LSD1 inhibitors' development.

Advances in the treatment of Langerhans cell histiocytosis (LCH) have resulted in a growing survivor population. There is a lack of data on long-term outcomes among adults with LCH. We conducted a retrospective record review of 219 adults (aged ≥18 years) with LCH. Most common presentation was multisystem (34.2%), followed by single-system pulmonary (32%), unifocal (28.3%), and single-system multifocal (5.5%) LCH. Risk organ involvement (the liver, spleen, or bone marrow) was seen in 8.7% of cases, and 40 of 88 (45.5%) tested cases were BRAFV600E. At a median follow-up of 74 months, 5-year progression-free survival (PFS) was 58.3% and estimated median PFS was 83 months. Median overall survival (OS) was not reached; 5- and 10-year OS rates were 88.7% and 74.5%, respectively. Risk organ involvement was associated with worse PFS (hazard ratio [HR], 4.5) and OS (HR, 10.8). BRAFV600E was not associated with risk organ involvement or survival. When compared with matched unaffected US population, individuals with LCH had a significantly higher risk of overall mortality (standardized mortality ratio [SMR], 2.66), specifically among those aged <55 years at diagnosis (SMR, 5.94) and those with multisystem disease (SMR, 4.12). Second cancers occurred in 16.4% cases, including diverse hematologic and solid organ malignancies. LCH-associated deaths constituted 36.1% of deaths and occurred within 5 years of diagnosis. After 5 years, non-LCH causes of death, including second cancers, chronic obstructive pulmonary disease, and cardiovascular diseases, predominated. Our study highlights, to our knowledge, for the first time, that adults with LCH experience early and late mortality from non-LCH causes and the need for development of targeted survivorship programs to improve outcomes., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Nanotechnology is revolutionizing cancer therapy, and catalyzes the emerging of ion-involved cancer-therapeutic modality, which unfortunately suffers from undesirable nanocarriers for efficient intracellular ion delivery. To radically extricate from this critical issue, the glutathione (GSH)-responsive organosilica network is employed to lock the liquid drops at the nanoscale via a general bottom-up strategy to achieve the systemic delivery of "ion drugs". In this work, a sulfate radical generation donor (Na 2 S 2 O 8 ), as a paradigm "ion drug", is entrapped into this liquid nanoparticle for efficiently delivering to the tumor region. After further surface engineering with pH-responsive tannic acid-Fe 2+ framework, these liquid nanoparticles achieve tumor-microenvironmental pH/GSH-dual responsive ion release (Fe 2+ /Na + /S 2 O 8 2- ) after reaching the tumor sites, where the Fe 2+ further triggers S 2 O 8 2- to generate toxic •SO 4 - and •OH, effectively executing cancer cell ferroptosis (Fe 2+ , reactive oxygen species-ROS) and pyroptosis (Na + , ROS). Such a tumor-responsive/specific liquid nanoplatform is highly instructive for further ion-mediated nanomedicine and disease treatment., (© 2023 Wiley-VCH GmbH.)

T-LAK cell-oriented protein kinase (TOPK) potently promotes malignant proliferation of tumour cells and is considered as a maker of tumour progression. Psoriasis is a common inflammatory skin disease characterized by abnormal proliferation of keratinocytes. However, the role of TOPK in psoriasis has not been well elucidated. This study aims to investigate the expression and role of TOPK in psoriasis, and the role of TOPK inhibitor in psoriasis attenuation. Gene Expression Omnibus datasets derived from psoriasis patients and psoriatic model mice were screened for analysis. Skin specimens from psoriasis patients were collected for TOPK immunohistochemical staining to investigate the expression and localization of TOPK. Next, psoriatic mice model was established to further confirm TOPK expression pattern. Then, TOPK inhibitor was applied to investigate the role of TOPK in psoriasis progression. Finally, cell proliferation assay, apoptosis assay and cell cycle analysis were performed to investigate the potential mechanism involved. Our study showed that TOPK was upregulated in the lesions of both psoriasis patients and psoriatic model mice, and TOPK levels were positively associated with psoriasis progression. TOPK was upregulated in psoriatic lesions and expressed predominantly by epidermal keratinocytes. In addition, TOPK levels in epidermal keratinocytes were positively correlated with epidermal hyperplasia. Furthermore, topical application of TOPK inhibitor OTS514 obviously alleviated disease severity and epidermal hyperplasia. Mechanismly, inhibiting TOPK induces G2/M phase arrest and apoptosis of keratinocytes, thereby attenuating epidermal hyperplasia and disease progression. Collectively, this study identifies that upregulation of TOPK in keratinocytes promotes psoriatic progression, and inhibiting TOPK attenuates epidermal hyperplasia and psoriatic progression., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Little is known about the risk of post-COVID-19 multisystem inflammatory syndrome in children (MIS-C) in the setting of childhood cancer., Objective: To evaluate factors associated with MIS-C and describe the clinical course of COVID-19 in the setting of MIS-C., Design, Setting, and Participants: Multisite observational cohort study of a registry representing more than 100 US pediatric oncology sites. All included patients were registered between April 1, 2020, and May 18, 2022. Sites submitted deidentified data surrounding sociodemographics, cancer diagnosis and treatment, and COVID-19 course (symptoms, maximum support required, outcome). Patients with MIS-C (n = 24) were compared with matched controls (n = 96). Children (<21 years) with cancer who developed COVID-19 while receiving cancer treatment or within 1 year of completing treatment were characterized based on their development of MIS-C., Exposures: (1) Clinical and sociodemographic characteristics of children with cancer and COVID-19; and (2) MIS-C., Main Outcomes and Measures: (1) Development of MIS-C among children with cancer and COVID-19; and (2) symptoms and disease severity associated with MIS-C., Results: Among 2035 children with cancer and COVID-19, 24 (1.2%) developed MIS-C. COVID-19 occurred at a median (IQR) age of 12.5 (5.5-17.1) years in those with MIS-C and 11 (6-16) years among matched controls (P = .86). The majority of children with MIS-C had a hematologic cancer (83.3% [n = 20]), were publicly insured (66.7% [n = 16]), and were Hispanic (54.2% [n = 13]). Half (n = 12) had 1 or more noncancer comorbidity. Those with comorbidities were more likely to develop MIS-C than those without (odds ratio [OR], 2.5 [95% CI, 1.1-5.7]). Among children with MIS-C, 100% (n = 24) were admitted to the hospital and 54.2% (n = 13) to the intensive care unit (ICU), while COVID-19 contributed to the death of 20.1% (n = 5); cancer therapy was changed in 62.5% (n = 15). Compared with matched controls, those with MIS-C had higher odds of symptoms classified as systemic (OR, 4.7 [95% CI, 1.4-15.8]) or gastrointestinal (OR, 5.0 [95% CI, 1.7-14.6]) along with higher odds of hospitalization (OR, 42.9 [95% CI, 7.1-258]), ICU admission (OR, 11.4 [95% CI, 3.6-36.4]), and changes to cancer therapy (OR, 24.9 [95% CI, 6.5-94.8])., Conclusions and Relevance: In this cohort study among children with cancer and COVID-19, those with MIS-C had a more severe clinical course than those without MIS-C. The risk of MIS-C and its severity are important to consider as clinicians monitor patients with COVID-19. These findings can inform their conversations with families regarding COVID-19 risks and the benefits of prevention strategies that are pharmacologic (vaccination) and nonpharmacologic (masking), as well as treatment (antivirals, monoclonal antibodies).

Background: Basic resource needs related to transportation, housing, food, and medications are important social determinants of health and modifiable indicators of poverty, but their role in modifying the risk of frailty and health-related quality of life (HRQoL) remains unknown. The goal of our study was to examine the prevalence of unmet basic needs and their association with frailty and HRQoL in a cohort of older adults with cancer., Methods: The CARE registry prospectively enrolls older adults (≥60 years) with cancer. Assessments of transportation, housing, and material hardship were added to the CARE tool in 8/2020. The 44-item CARE Frailty Index was used to define frailty, and subdomains of physical and mental HRQoL were assessed using the PROMIS® 10-global. Multivariable analysis examined the association between unmet needs with frailty and HRQoL subdomains, adjusting for covariates., Results: The cohort included 494 participants. Median age of 69 years, 63.6% were male and 20.2% were Non-Hispanic (NH) Black. Unmet basic needs were reported in 17.8% (transportation 11.5%, housing 2.8%, and material hardship 7.5%). Those with unmet needs were more often NH Black (33.0% vs. 17.8%, p = 0.006) and less educated (

Insufficient hydrogen peroxide content in tumor cells, unsuitable pH and low efficiency of commonly used metal catalysts severely affect the efficiency of chemodynamic therapy, resulting in unsatisfactory efficacy of chemodynamic therapy alone. For this purpose, we designed a composite nanoplatform capable of targeting tumors and selectively degrading in the tumor microenvironment (TME) to address these issues. In this work, we synthesized Au@Co 3 O 4 nanozyme inspired by crystal defect engineering. The addition of Au determines the formation of oxygen vacancies, accelerates electron transfer, and enhances redox activity, thus significantly enhancing the superoxide dismutase (SOD)-like and catalase (CAT)-like catalytic activities of the nanozyme. Subsequently, we camouflaged the nanozyme using a biomineralized CaCO 3 shell to avoid damage to normal tissues by the nanozyme while effectively encapsulating the photosensitizer IR820, and finally the tumor targeting ability of the nanoplatform was enhanced by the modification of hyaluronic acid. Under near-infrared (NIR) light irradiation, the Au@Co 3 O 4 @CaCO 3 /IR820@HA nanoplatform not only visualizes the treatment with multimodal imaging, but also plays a photothermal sensitizing role through various strategies, while enhancing the enzyme catalytic activity, cobalt ion-mediated chemodynamic therapy (CDT) and IR820-mediated photodynamic therapy (PDT), and achieving the synergistic enhancement of reactive oxygen species (ROS) generation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Singlet oxygen ( 1 O 2 ) has received considerable research attention in photodynamic therapy (PDT) due to its cytotoxic solid features. However, the inherent hypoxic state of the tumor microenvironment (TME) leads to the meager 1 O 2 quantum yield of inorganic PDT reagents, and their application in vivo remains elusive. Methods: We developed a novel strategy to fabricate active photosynthetic bacteria/photosensitizer/photothermal agent hybrids for photosynthetic tumor oxygenation and PDT and PTT tumor therapy under different laser irradiation sources. Photosynthetic bacteria combined with Ce6 photosensitizer and Au NPs photothermal agent, the obtained Bac@Au-Ce6 effectively targets tumor tissues and further enhances the tumor accumulation of Au-Ce6. Results: The results showed that the Au-Ce6-loaded engineered bacteria (Bac@Au-Ce6) maintained the photosynthetic properties of Syne . After i.v. injection, Bac@Au-Ce6 efficiently aggregates at tumor sites due to the tumor-targeting ability of active Syne . With 660 nm laser irradiation at the tumor site, the photoautotrophic Syne undergoes sustained photosynthetic O 2 release and immediately activates O 2 to 1 O 2 via a loaded photosensitizer. PTT was subsequently imparted by 808 laser irradiations to enhance tumor killing further. Conclusions: This work provides a new platform for engineering bacteria-mediated photosynthesis to promote PDT combined with PTT multi-faceted anti-tumor., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: One-fifth of U.S. counties are designated persistent child poverty counties (≥20% of children in poverty since 1980). The association between a persistent child poverty environment and mortality in children with cancer is unknown., Methods: Our cohort includes 2,089 children with cancer (2000-2016) in Alabama. We used multivariable Cox proportional hazards modeling (adjusted for sociodemographics/clinical characteristics) to assess mortality by persistent child poverty designation at 1, 5, and 10 years from diagnosis. Distance to treatment was subsequently explored., Results: Forty-two percent of the cohort lived in a persistent child poverty county; they were more likely to be African American (P < 0.0001), have public/no insurance (P = 0.0009), and live >100 miles to treatment (P < 0.0001). Children in persistent child poverty counties were 30% more likely to die by 5 years [95% confidence interval (CI) = 1.06-1.59; P = 0.012]. Distance (per 20-mile increase) to treatment was associated with a 9% increased mortality risk (P < 0.0001). Children with both exposures (distance >100 miles and persistent child poverty) faced the highest mortality risk at 5 years (HR = 1.80; 95% CI = 1.39-2.33; P < 0.0001). In subanalysis, children exposed to persistent child poverty were at higher risk for cancer-related mortality. However, the risk of health-related mortality did not differ., Conclusions: Among children with cancer from the Deep South, persistent child poverty was a prevalent exposure associated with inferior overall survival. Distance to treatment was independently associated with inferior survival. Children with both exposures had the highest risk of mortality., Impact: Persistent child poverty is associated with inferior survival among children with cancer; mechanisms underlying this disparity warrant investigation. See related commentary by Orjuela-Grimm and Beauchemin, p. 295., (©2022 American Association for Cancer Research.)

Importance: Survivors of blood or marrow transplant (BMT) are at increased risk of subsequent malignant neoplasms (SMNs). Cancers of the gastrointestinal (GI) system are of special interest because their clinical behavior is often aggressive, necessitating early detection by increasing awareness of high-risk populations., Objective: To describe the risk of SMNs in the GI tract after BMT., Design, Setting, and Participants: A cohort study of 6710 individuals who lived at least 2 years after BMT performed between January 1, 1974, and December 31, 2014, at City of Hope, University of Minnesota, or University of Alabama at Birmingham. End of follow-up was March 23, 2020. Data analysis was performed between September 1, 2022, and September 30, 2022., Exposures: Demographic and clinical factors; therapeutic exposures before or as part of BMT., Main Outcomes and Measures: Development of SMNs in the GI tract after BMT. Participants self-reported SMNs in the GI tract; these were confirmed with pathology reports, medical records, or both. For deceased patients, death records were used. Standardized incidence ratios determined excess risk of SMNs in the GI tract compared with that of the general population. Fine-Gray proportional subdistribution hazard models assessed the association between risk factors and SMNs in the GI tract., Results: The cohort of 6710 individuals included 3444 (51.3%) autologous and 3266 (48.7%) allogeneic BMT recipients. A total of 3917 individuals (58.4%) were male, and the median age at BMT was 46 years (range, 0-78 years). After 62 479 person-years of follow-up, 148 patients developed SMNs in the GI tract. The standardized incidence ratios for developing specific SMNs ranged from 2.1 for colorectal cancer (95% CI, 1.6-2.8; P < .001) to 7.8 for esophageal cancer (95% CI, 5.0-11.6; P < .001). Exposure to cytarabine for conditioning (subdistribution hazard ratio [SHR], 3.1; 95% CI, 1.5-6.6) was associated with subsequent colorectal cancer. Compared with autologous BMT recipients, allogeneic BMT recipients with chronic graft-vs-host disease were at increased risk for esophageal cancer (SHR, 9.9; 95% CI, 3.2-30.5). Conditioning with etoposide (SHR, 2.0; 95% CI, 1.1-3.5) and pre-BMT anthracycline exposure (SHR, 5.4; 95% CI, 1.3-23.4) were associated with an increased risk of liver cancer compared with no exposure to the respective agents., Conclusions and Relevance: The findings of this cohort study are relevant for oncologists and nononcologists who care for the growing number of survivors of transplant. Awareness of subgroups of survivors of BMT at high risk for specific types of SMNs in the GI tract may influence recommendations regarding modifiable risk factors, as well as individualized screening.

Enhanced imaging techniques using contrast agents enable high-resolution structural imaging to reveal space-occupying lesions but rarely provide detailed molecular information. To this end, we report a structural and molecular fusion magnetic resonance imaging (MRI) nanoprobe for differential diagnosis between benign and malignant tumors. This fusion nanoprobe, termed FFT NPs, follows a working mechanism involving a T 1 -/ T 2 -weighted magnetic resonance tuning effect (MRET) between a magnetic Fe 3 O 4 core and a paramagnetic Fe-tannic acid (Fe-TA) shell. The FFT NPs with an "always-on" inert T 2 signal provide structural MRI (sMRI) contrast of tumors while affording an activated T 1 signal in the presence of ATP, which is overproduced during the rapid growth of malignant tumors to enable molecular MRI (mMRI) of tumor lesions. We propose the use of the ratiometric mMRI:sMRI intensity to assist in the differential diagnosis of malignant 4T1 tumors from benign L929 fibroblast tumors. Furthermore, the dissociated FFT NPs were found to be able to catalyze H 2 O 2 conversion in 4T1 tumors to generate excess reactive oxygen species (ROS) for chemodynamic therapy. The described fusion nanoprobe strategy enables the differential diagnosis of tumors from a combined spatial and molecular perspective with one-stop MRI imaging with potential applications in precision intervention.

Drug response prediction in cancer cell lines is of great significance in personalized medicine. In this study, we propose GADRP, a cancer drug response prediction model based on graph convolutional networks (GCNs) and autoencoders (AEs). We first use a stacked deep AE to extract low-dimensional representations from cell line features, and then construct a sparse drug cell line pair (DCP) network incorporating drug, cell line, and DCP similarity information. Later, initial residual and layer attention-based GCN (ILGCN) that can alleviate over-smoothing problem is utilized to learn DCP features. And finally, fully connected network is employed to make prediction. Benchmarking results demonstrate that GADRP can significantly improve prediction performance on all metrics compared with baselines on five datasets. Particularly, experiments of predictions of unknown DCP responses, drug-cancer tissue associations， and drug-pathway associations illustrate the predictive power of GADRP. All results highlight the effectiveness of GADRP in predicting drug responses, and its potential value in guiding anti-cancer drug selection., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Iron accumulation and lipid peroxidation form the basis of ferroptosis, potentially circumventing the limitations of apoptosis in cancer treatment. Owing to the lack of potent ferroptosis inducers, the development of efficient ferroptosis-based therapeutic agents and protocols against cancers is highly challenging. Inspired by the topological effect of nanoparticles in modulating cellular function/status, a specific tetrapod ferroptosis-inducer iron-palladium (FePd) nanocrystal was rationally engineered for physically activated autophagy-augmented ferroptosis and enhanced cancer immunotherapy. Specifically, the tetrapod FePd nanocrystal featured strong peroxidase-/glutathione oxidase-mimicking bioactivities, which promoted cancer cell ferroptosis. The special spiky morphology and nanostructure of the FePd nanocrystal simultaneously induced autophagy, which augmented ferroptosis in cancer cells and triggered the release of inflammatory cytokines in macrophages for strengthening anti-PD-L1-antibody mediated immunotherapy, synergistically achieving the maximal antineoplastic effect in three tumor-bearing animal models. This unique physical activation strategy for efficient cancer treatment via precise morphological tuning represents a paradigm for nanomedicine design for efficient tumor treatment., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2022 Science China Press. Published by Elsevier B.V. All rights reserved.)

Sonosensitizers that can increase the concentration of reactive oxygen species (ROS) within a tumor microenvironment is a high priority for sonodynamic therapy (SDT). In this study, a functionalized, smart nanosonosensitizer based on Au-RuO 2 nanoparticles (NPs) and selenium nanoparticles (Se NPs) that were electrostatically self-assembled onto the surface of Listeria innocua (LI) was used to create Bac@ARS. Au NPs provided the core in which RuO 2 was deposited to form Au-RuO 2 NPs. Additionally, the underlying properties of the Au NPs and Se NPs were used to optimize the sonosensitivity performance. Compared with pristine RuO 2 NPs, Bac@ARS exhibits highly efficient ROS-producing activity. Furthermore, Bac@ARS remodeled the hypoxic tumor microenvironment, enabling overproduction of ROS. Importantly, Bac@ARS exploits the natural tropism of LI to selectively accumulate in tumors, which improved the treatment precision at hypoxic tumor sites after sonodynamic activation. However, the activity of LI was greatly reduced after ultrasound (US) irradiation, ensuring the biosafety of Bac@ARS. Bac@ARS was also used to monitor tumors, in real time, using photoacoustic imaging of the gold-based nanoparticles. Therefore, Bac@ARS is a promising microbial sonosensitizer providing a new platform for the optimization of sonosensitizers for tumor treatment. STATEMENT OF SIGNIFICANCE: A bio-nano-sonosensitizer was designed using a Au nanoparticle (NP) core modified with RuO 2 NPs. The Au-RuO 2 NPs together with Se-NPs are attached via electrostatic adsorption to a live bacterium Listeria innocua (LI), creating Bac@ARS. The role of the NPs was to optimize the sonosensitivity performance at the target tumor site. Bac@ARS reshaped the tumor microenvironment and overcame tumor hypoxia leading to ROS overproduction. This activated a potent ICD-mediated cellular immunity and anti-tumor activity. Importantly, Bac@ARS exploited the natural tropism of LI to selectively accumulate in tumors, resulting in more precise delivery of the therapeutic effect while exhibiting reduced effects on healthy tissues., 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 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: Individuals diagnosed with cancer age between 15 and 39 years (adolescents and young adults [AYAs]) have not seen improvement in survival compared with children or older adults; clinical trial accrual correlates with survival. Unique unmet needs among AYAs related to psychosocial support and fertility preservation (FP) are associated with health-related quality of life., Methods: We enhanced existing structures and leveraged faculty/staff across pediatric/adult oncology to create novel teams focused on AYA (age 15-39 years) care at a single center, with minimal dedicated staff and no change to revenue streams. We aimed to influence domains shown to drive survival and health-related quality of life: clinical trial enrollment, physician/staff collaboration, psychosocial support, and FP. We captured metrics 3 months after patients presented to the institution and compared them before/after Program implementation using descriptive statistics., Results: Among 139 AYAs (age 15-39 years) from the pre-Program era (January 2016-February 2019: adult, n = 79; pediatric, n = 60), and 279 from the post-Program era (February 2019-March 2022: adult, n = 215; pediatric, n = 64), there was no change in clinical trial enrollment( P ≥ .3), whereas there was an increase in the proportion of AYAs referred for supportive care and psychology (pediatric: P ≤ .02; adult: P ≤ .001); whose oncologists discussed FP (pediatric: 15% v 52%, P < .0001; adult: 37% v 50%, P = .0004); and undergoing FP consults (pediatric: 8% v 39%, P < .0001; adult 23% v 38%, P = .02)., Conclusion: This team-based framework has effected change in most targeted domains. To affect all domains and design optimal interventions, it is crucial to understand patient-level and facility-level barriers/facilitators to FP and clinical trial enrollment.

CD137 (4-1BB, TNFRSF9), an inducible T-cell costimulatory receptor, is expressed on activated T cells, activated NK cells, Treg cells, and several innate immune cells, including DCs, monocytes, neutrophils, mast cells, and eosinophils. In animal models and clinical trials, anti-CD137 agonistic monoclonal antibodies have shown anti-tumor potential, but balancing the efficacy and toxicity of anti-CD137 agonistic monoclonal antibodies is a considerable hindrance for clinical applications. Here, we describe a novel fully human CD137 agonistic antibody (PE0116) generated from immunized harbor H2L2 human transgenic mice. PE0116 is a ligand blocker, which is also the case for Utomilumab (one of the leading CD137 agonistic drugs); PE0116 partially overlaps with Urelumab's recognized epitope. In vitro, PE0116 activates NF-κB signaling, significantly promotes T-cell proliferation, and increases cytokine secretion in the presence of cross-linking. Importantly, PE0116 possesses robust anti-tumor activity in the MC38 tumor model. In vivo, PE0116 exhibits a good safety profile and has typical pharmacokinetic characteristics of an IgG antibody in preclinical studies of non-human primates. In summary, PE0116 is a promising anti-CD137 antibody with a good safety profile in preclinical studies., (© 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Chimeric antigen receptor (CAR) T-cell therapy has emerged recently as a standard of care treatment for patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and several subtypes of B-cell non-Hodgkin lymphoma (NHL). However, its use remains limited to highly specialized centers, given the complexity of its administration and its associated toxicities. We previously reported our experience in using a novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy in the peri-transplant setting, where it exhibited an excellent safety profile with encouraging survival outcomes. We have since modified the SB CD19 CAR construct to improve its efficacy and shorten its manufacturing time. We report here the phase 1 clinical trial safety results. Fourteen heavily treated patients with relapsed/refractory ALL and NHL were infused. Overall, no serious adverse events were directly attributed to the study treatment. Three patients developed grades 1-2 cytokine release syndrome and none of the study patients experienced neurotoxicity. All dose levels were well tolerated and no dose-limiting toxicities were reported. For efficacy, 3 of 8 (38%) patients with ALL achieved CR/CRi (complete remission with incomplete count recovery) and 1 (13%) patient had sustained molecular disease positivity. Of the 4 patients with DLBCL, 2 (50%) achieved CR. The SB-based CAR constructs allow manufacturing of targeted CAR T-cell therapies that are safe, cost-effective and with encouraging antitumor activity., Competing Interests: The technology was advanced through research conducted at MD Anderson by LC. In January 2015, the technology was licensed by The University of Texas MD Anderson Cancer Center for commercial application to Alaunos Therapeutics formerly Ziopharm Oncology, Inc., and Precigen formerly Intrexon Corporation, in exchange for equity interests in each of these companies. LC and some co-authors received equity because of the licensing of this technology. From 2015 to 2021 LC was Chief Executive Officer at ZIOPHARM. The information being reported in this publication is research in which The University of Texas MD Anderson Cancer Center has an institutional financial conflict of interest. Because The University of Texas MD Anderson Cancer Center is committed to the protection of human subjects and the effective management of its financial conflicts of interest in relation to its research activities, The University of Texas MD Anderson Cancer Center has implemented an Institutional Conflict of Interest Management and Monitoring Plan to manage and monitor the conflict of interest with respect to The University of Texas MD Anderson Cancer Center’s conduct of this research. EG and LC were formerly employed by Alaunos Therapeutics and have equity ownership in the company. KR and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Takeda Pharmaceutical and Affimed GmbH. KR participates on the Scientific Advisory Board for GemoAb, AvengeBio, Virogin Biotech, GSK, Bayer, Navan Technologies, and Caribou Biosciences. ES participates on Scientific Advisory Boards for Adaptimmune, Axio, Navan, Fibroblasts and Fibrobiologics, and the NY Blood Center; has licensing or patents with Takeda and Affimed; and honorarium from Bayer Healthcare Pharmaceuticals. PK has served on advisory boards for Kite and Pfizer; received research support from Amgen and Alaunos; and has been a consultant for Jazz. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Singh, Srour, Milton, McCarty, Dai, Gaballa, Ammari, Olivares, Huls, De Groot, Marin, Petropoulos, Olson, Anderlini, Im, Khouri, Hosing, Rezvani, Champlin, Shpall, Cooper and Kebriaei.)

Background: Considering the heterogeneity of tumors, it is a key issue in precision medicine to predict the drug response of each individual. The accumulation of various types of drug informatics and multi-omics data facilitates the development of efficient models for drug response prediction. However, the selection of high-quality data sources and the design of suitable methods remain a challenge., Methods: In this paper, we design NeRD, a multidimensional data integration model based on the PRISM drug response database, to predict the cellular response of drugs. Four feature extractors, including drug structure extractor (DSE), molecular fingerprint extractor (MFE), miRNA expression extractor (mEE), and copy number extractor (CNE), are designed for different types and dimensions of data. A fully connected network is used to fuse all features and make predictions., Results: Experimental results demonstrate the effective integration of the global and local structural features of drugs, as well as the features of cell lines from different omics data. For all metrics tested on the PRISM database, NeRD surpassed previous approaches. We also verified that NeRD has strong reliability in the prediction results of new samples. Moreover, unlike other algorithms, when the amount of training data was reduced, NeRD maintained stable performance., Conclusions: NeRD's feature fusion provides a new idea for drug response prediction, which is of great significance for precise cancer treatment., (© 2022. The Author(s).)

Purpose: Identifying older patients with GI malignancies who are at increased risk of mortality remains challenging. The goal of our study was to examine geriatric assessment (GA) predictors of 1-year mortality and explore the use of a survival tree analysis in a prospective cohort of older adults (≥ 60 years) with newly diagnosed GI malignancies., Methods: Survival tree analysis was performed to understand variable interactions and identify predictors of overall survival, computed from time of GA to death or last follow-up. Cox regression was used to estimate associations of 1-year mortality, first using a base model (age, race, cancer stage, cancer risk group, and planned chemotherapy), then using all significant predictors from the univariable analyses, and finally only those identified in survival tree analysis., Results: A total of 478 participants met eligibility, with a mean age of 70 years. The survival tree analysis identified nutrition, cancer stage, physical and emotional health, age, and functional status as predictors of mortality. Older patients without malnutrition or depression had the best 1-year survival, whereas those with malnutrition, stage IV disease, and functional limitations had the worst 1-year survival. Our base model demonstrated good discrimination (area under curve [AUC] 0.76) but was improved with the addition of GA variables (AUC 0.82) or from survival tree analysis (AUC 0.82)., Conclusion: Measures of function, nutrition, and mental health are important predictors of mortality in older adults with GI cancers. Using GA as part of clinical management can aid in the prediction of survival and help inform treatment decision making., Competing Interests: Grant R. WilliamsHonoraria: Cardinal Health Smith GiriHonoraria: CareVive, OncLive, SanofiResearch Funding: CareVive Systems, Pack Health, Sanofi (Inst) Andrew McDonaldConsulting or Advisory Role: Varian Medical SystemsResearch Funding: Varian Medical Systems (Inst), Collegium (Inst) Olumide GbolahanStock and Other Ownership Interests: PfizerConsulting or Advisory Role: Merck Sharp & Dohme, Exelixis, Incyte, QED TherapeuticsSpeaker's Bureau: OncLive/MJH Life SciencesResearch Funding: AstraZeneca/MedImmune (Inst) Darryl OutlawHonoraria: OncLive/MJH Life Sciences Moh'd KhushmanStock and Other Ownership Interests: Halozyme, Guardant Health, Aprea Therapeutics, Blueprint Medicines, Daiichi Sankyo, Global Blood Therapeutics, Cardiff Oncology, Moderna Therapeutics, RegeneronConsulting or Advisory Role: AstraZeneca, Taiho Pharmaceutical, BayerSpeaker's Bureau: AstraZeneca, PfizerNo other potential conflicts of interest were reported.

Purpose: We determined trends in life expectancy and cause-specific late mortality after autologous blood or marrow transplantation (BMT) performed over a 30-year period, using the BMT Survivor Study., Methods: We constructed a cohort of 4,702 individuals with hematologic neoplasms who lived ≥ 2 years after autologous BMT performed between 1981 and 2014 at three transplant centers. The end of follow-up was April 19, 2021. The primary exposure variable was autologous BMT performed in four eras: 1981-1999; 2000-2005; 2006-2010; and 2011-2014. Vital status and cause of death were obtained from National Death Index Plus program and Accurinct databases., Results: The median age at BMT was 53 years (range, 0-78 years), 58.7% were male, 67.8% were non-Hispanic White, and 28.3% had undergone transplantation between 2011 and 2014. Autologous BMT recipients experienced a 7-year reduction in life expectancy. The adjusted hazard of 5-year all-cause mortality declined over the four eras (reference: 1981-1999; hazard ratio [HR] 2000-2005 = 0.77; 95% CI, 0.62 to 0.94; HR 2006-2010 = 0.64; 95% CI, 0.51 to 0.79; HR 2011-2014 = 0.56; 95% CI, 0.45 to 0.71; P trend < .0001; primarily for BMTs before 2006) and subsequent neoplasms ( P trend < .0001; primarily for BMTs before 2006) and subsequent neoplasms ( P trend = .03; confined to decline in therapy-related myeloid neoplasm-related mortality) but not because of cardiovascular or renal disease., Conclusion: Late mortality among autologous BMT recipients has declined over a 30-year period. However, ongoing efforts are needed to mitigate development of infections, subsequent neoplasms, and cardiovascular and renal disease to further reduce late mortality., Competing Interests: Smita BhatiaThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript. Wendy LandierResearch Funding: Merck Sharp & Dohme (Inst) Stephen J. FormanStock and Other Ownership Interests: MustangBio, Lixte BiotechnologyConsulting or Advisory Role: Alimera Sciences, Lixte Biotechnology, MustangBioResearch Funding: MustangBioPatents, Royalties, Other Intellectual Property: MustangBio Daniel J. WeisdorfConsulting or Advisory Role: Incyte, Fate TherapeuticsResearch Funding: Incyte Mukta AroraConsulting or Advisory Role: Fate TherapeuticsResearch Funding: Syndax (Inst), Kadmon (Inst), Pharmacyclics (Inst)No other potential conflicts of interest were reported.

Synthetic lethality (SL) occurs between two genes when the inactivation of either gene alone has no effect on cell survival but the inactivation of both genes results in cell death. SL-based therapy has become one of the most promising targeted cancer therapies in the last decade as PARP inhibitors achieve great success in the clinic. The key point to exploiting SL-based cancer therapy is the identification of robust SL pairs. Although many wet-lab-based methods have been developed to screen SL pairs, known SL pairs are less than 0.1% of all potential pairs due to large number of human gene combinations. Computational prediction methods complement wet-lab-based methods to effectively reduce the search space of SL pairs. In this paper, we review the recent applications of computational methods and commonly used databases for SL prediction. First, we introduce the concept of SL and its screening methods. Second, various SL-related data resources are summarized. Then, computational methods including statistical-based methods, network-based methods, classical machine learning methods and deep learning methods for SL prediction are summarized. In particular, we elaborate on the negative sampling methods applied in these models. Next, representative tools for SL prediction are introduced. Finally, the challenges and future work for SL prediction are discussed., (© The Author(s) 2022. Published by Oxford University Press.)

Using biocompatible polymers with potential therapeutic activity is an appealing strategy for the development of new functional drug carriers. In this study, we report the synthesis of therapeutic poly( p -coumaric acid) (PCA) from p -coumaric acid, a common plant phenolic acid with multiple bioactivities. The prepared PCA was formulated into nanoparticles (NPs) using the nanoprecipitation method and docetaxel (DTX) was encapsulated to form DTX-loaded PCA NPs (DTX@PCA NPs). Their potential as a nanocarrier for anticancer drug delivery was systematically evaluated. The DTX@PCA NPs not only had a small particle size and good stability, but also exhibited superior in vitro anticancer activity, anti-metastasis ability compared with free drugs, and preferable cellular uptake by tumor cells. In addition, the three-dimensional tumor spheroid assay revealed the effective tumor penetration and anticancer activity of the DTX@PCA NPs. Importantly, the DTX@PCA NPs preferentially accumulated in tumors and prolonged systemic circulation, significantly inhibiting tumor growth in vivo and simultaneously attenuating the side effects of DTX. Interestingly, the blank PCA NPs themselves also exhibited additional tumor suppression activity to some extent with high biosafety, further indicating the significant potential of PCA as a novel self-therapeutic nanocarrier for anticancer drug delivery and enhanced cancer therapy.

The pursuing of photosensitizers (PSs) with efficient reactive oxygen species (ROS) especially type I ROS generation in aggregate is always in high demand for photodynamic therapy (PDT) and photoimmunotherapy but remains to be a big challenge. Herein, we report a cationization molecular engineering strategy to boost both singlet oxygen and radical generation for PDT. Cationization could convert the neutral donor-acceptor (D-A) typed molecules with the dicyanoisophorone-triphenylamine core (DTPAN, DTPAPy) to their A-D-A' typed cationic counterparts (DTPANPF 6 and DTPAPyPF 6 ). Our experiment and simulation results reveal that such cationization could enhance the aggregation-induced emission (AIE) feature, promote the intersystem crossing (ISC) processes, and increase the charge transfer and separation ability, all of which work collaboratively to promote the efficient generation of ROS especially hydroxyl and superoxide radicals in aggregates. Moreover, these cationic AIE PSs also possess specific cancer cell mitochondrial targeting capability, which could further promote the PDT efficacy both in vitro and in vivo. Therefore, we expect this delicate molecular design represents an attractive paradigm to guide the design of type I AIE PSs for the further development of PDT., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Downregulation of PTENP1 was reported in different malignant tumors. However, the function and significance of PTENP1 in the clinical pathology and prognosis of tumors are not very clear. Therefore, we performed this research to analyze and elucidate the correlations between the PTENP1 expression and clinical pathological parameters and outcome of patients in different types of cancer., Methods: Literature on PTENP1 was retrieved from PubMed, EMBASE, Web of Science, Cochrane Library, CNKI, Wan Fang, Springer, Ovid, and Medline databases. Pooled ORs (odds ratios) or HRs (hazard ratios) with 95% CIs were utilized to examine the relationship between the PTENP1 and clinical pathological traits and outcome of patients with different tumor types., Results: Eight studies comprising 1,047 patients were enrolled and analyzed in this research. Down-regulation of PTENP1 was correlated with differentiation (OR: 2.57; 95% CI: 1.14 - 5.80), TNM stage (OR: 0.24; 95% CI: 0.13 - 0.43), and LNM (OR: 0.27; 95% CI: 0.14 - 0.52). Moreover, PTENP1 expression level was correlated with OS in the eight types of tumors (pooled HR: 0.49; 95% CI: 0.39, 0.61)., Conclusions: Low expression of PTENP1 might predict poor prognosis in patients with various carcinomas. PTENP1 may play an important role as a new prognostic indicator in patients with different malignant tumors.

The recent discovery of immune checkpoint inhibitors is a significant milestone in cancer immunotherapy research. However, some patients with primary or adaptive drug resistance might not benefit from the overall therapeutic potential of immunotherapy in oncology. Thus, it is becoming increasingly critical for oncologists to explore the availability of new immune checkpoint inhibitors. An emerging co-inhibitory receptor, CD112R (also called PVRIG), is most commonly expressed on natural killer (NK) and T cells. It binds to its ligand (CD112 or PVRL2/nectin-2) and inhibits the strength with which T cells and NK cells respond to cancer. Therefore, CD112R is being presented as a new immune checkpoint inhibitor with high potential in cancer immunotherapy. CD112 is easily detectable on antigen-presenting or tumor cells, and its high level of expression has been linked with tumor progression and poor outcomes in most cancer patients. This review explores the molecular and functional relationship between CD112R, TIGIT, CD96, and CD226 in T cell responses. In addition, this review comprehensively discusses the recent developments of CD112R/CD112 immune checkpoints in cancer immunotherapy and prognosis., (© 2021. The Author(s).)

At present, tumor diagnosis is performed using common procedures, which are slow, costly, and still presenting difficulties in diagnosing tumors at their early stage. Tumor therapeutic methods also mainly rely on large-scale equipment or non-intelligent treatment approaches. Thus, an early and accurate tumor diagnosis and personalized treatment may represent the best treatment option for a successful result, and the efforts in finding them are still in progress and mainly focusing on non-destructive, integrated, and multiple technologies. These objectives can be achieved with the development of advanced devices and smart technology that represent the topic of the current investigations. Therefore, this review summarizes the progress in tumor diagnosis and therapy and briefly explains the advantages and disadvantages of the described microdevices, finally proposing advanced micro smart devices as the future development trend for tumor diagnosis and therapy., (© 2021 Wiley-VCH GmbH.)

Background: Sarcopenia is associated with adverse outcomes among older adults with cancer; however, no easily applied sarcopenia measure exists for use in clinical practice. The use of SARC-F, a 5-item self-reported sarcopenia screening questionnaire, among older adults with cancer remains to be investigated., Methods: Older adults (aged ≥60 years) with cancer enrolled in the University of Alabama Cancer and Aging Resilience Evaluation Registry were identified. Patients completed the SARC-F questionnaire (with scores ≥4 considered positive for sarcopenia). The authors assessed for differences in geriatric assessment domain impairments, health-related quality of life, and health care utilization between those with and without sarcopenia using multivariate regression, then assessed the association of sarcopenia with survival using Kaplan-Meier methods and a Cox regression model, adjusting for covariates., Results: In total, 256 older adults were identified. The median age was 69 years, 59% of participants were men, and 75% were White. The median SARC-F score was 2 (interquartile range, 0-4), and 33% of participants screened positive. Those with sarcopenia had higher odds of having multiple impairments, including impaired instrumental activities of daily living (adjusted odds ratio [aOR], 18.1; 95% CI, 7.5-43.8) and frailty (aOR, 43.5; 95% CI, 17.7-106.8) as well as reduced physical and mental health-related quality of life (β coefficient, -13.6 and -11.5, respectively) and increased emergency room visits (aOR, 2.4; 95% CI, 1.3-4.7). Furthermore, sarcopenia was independently associated with inferior overall survival (adjusted hazard ratio, 2.98; 95% CI, 1.1-8.3; P = .04)., Conclusions: One-third of older adults with cancer in this cohort screened positive for sarcopenia using the SARC-F screening questionnaire, and these positive scores are associated with geriatric assessment domain impairments, reduced health-related quality of life, increased emergency room visits, and inferior overall survival., (© 2020 American Cancer Society.)

Background: Cancer of unknown primary (CUP) is a type of malignant tumor, which is histologically diagnosed as a metastatic carcinoma while the tissue-of-origin cannot be identified. CUP accounts for roughly 5% of all cancers. Traditional treatment for CUP is primarily broad-spectrum chemotherapy; however, the prognosis is relatively poor. Thus, it is of clinical importance to accurately infer the tissue-of-origin of CUP., Methods: We developed a gradient boosting framework to trace tissue-of-origin of 20 types of solid tumors. Specifically, we downloaded the expression profiles of 20,501 genes for 7713 samples from The Cancer Genome Atlas (TCGA), which were used as the training data set. The RNA-seq data of 79 tumor samples from 6 cancer types with known origins were also downloaded from the Gene Expression Omnibus (GEO) for an independent data set., Results: 400 genes were selected to train a gradient boosting model for identification of the primary site of the tumor. The overall 10-fold cross-validation accuracy of our method was 96.1% across 20 types of cancer, while the accuracy for the independent data set reached 83.5%., Conclusion: Our gradient boosting framework was proven to be accurate in identifying tumor tissue-of-origin on both training data and independent testing data, which might be of practical usage., Competing Interests: There is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Ruixi Li et al.)

The rapid development of nanotechnology has triggered the emerging of tremendous theranostic nanoplatforms for combating cancers. Silicene, as an emerging two-dimensional (2D) material, has been recently explored as therapeutic agent due to their desirable biodegradation and strong photothermal-conversion performance. However, the rational design of silicene-based composites for further exerting multifunctional medical applications is still highly challenging. Herein, we report on the construction of silicene-based silicene@Pt composite nanosheets for computed tomography (CT)/photoacoustic (PA) imaging-guided dual-sensitized radiotherapy combined with photonic tumor hyperthermia, which has been achieved by a seed-growth approach to in situ grow Pt components onto silicene nanosheets' surface. Especially, by functionalization of Pt components, these nanosheets could act as both contrast agents for CT imaging and dual radio-sensitizing agents for radiotherapy, which could deposit Pt-involved radiation energy (sensitized therapeutic process I) and overcome hypoxia-associated radio-resistance by Pt-catalytic O 2 generation from overexpressed H 2 O 2 within the tumor microenvironment (sensitized therapeutic process II). The strong photothermal-conversion performance of silicene nanosheets not only endowed silicene@Pt composite nanosheets with photoacoustic imaging property, but also realized the photonic tumor hyperthermia and achieved a combined therapeutic effect with radiotherapy. This work not only broadens the biomedical applications of silicene, but also develops functionalization strategies of silicene for versatile biomedical applications., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Tumor-associated macrophages (TAMs) are vital constituents in mediating cell-to-cell communication within the tumor microenvironment. However, the molecular mechanisms underlying the interplay between TAMs and tumor cells that guide cell fate are largely undetermined. Extracellular vesicles, also known as exosomes, which are derived from TAMs, are the components exerting regulatory effects. Thus, understanding the underlying mechanism of "onco-vesicles" is of crucial importance for prostate cancer (PCa) therapy. In this study, we analyzed micro RNA sequences in exosomes released by THP-1 and M2 macrophages and found a significant increase in miR-95 levels in TAM-derived exosomes, demonstrating the direct uptake of miR-95 by recipient PCa cells. In vitro and in vivo loss-of-function assays suggested that miR-95 could function as a tumor promoter by directly binding to its downstream target gene, JunB, to promote PCa cell proliferation, invasion, and epithelial-mesenchymal transition. The clinical data analyses further revealed that higher miR-95 expression results in worse clinicopathological features. Collectively, our results demonstrated that TAM-mediated PCa progression is partially attributed to the aberrant expression of miR-95 in TAM-derived exosomes, and the miR-95/JunB axis provides the groundwork for research on TAMs to further develop more-personalized therapeutic approaches for patients with PCa., (© 2020 Wiley Periodicals LLC.)

Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK's potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

Background: Circulating tumor DNA (ctDNA) offers a convenient way to monitor tumor progression and treatment response. Because tumor mutational profiles are highly variable from person to person, a fixed content panel may be insufficient to track treatment response in all patients., Methods: We design ctDNA fingerprint panels specific to individual patients which are based on whole exome sequencing and target to high frequency clonal population clusters in patients. We test the fingerprint panels in 313 patients who together have eight tumor types (colorectal, hepatocellular, gastric, breast, pancreatic, and esophageal carcinomas and lung cancer and cholangiocarcinoma) and exposed to multiple treatment methods (surgery, chemotherapy, radiotherapy, targeted-drug therapy, immunotherapy, and combinations of them). We also monitor drug-related mutations in the patients using a pre-designed panel with eight hotspot genes., Results: 291 (93.0%) designed fingerprint panels harbor less than ten previously known tumor genes. We detected 7475 ctDNA mutations in 238 (76%) patients and 6196 (96.0%) of the mutations are detected in only one test. Both the level of ctDNA content fraction (CCF) and fold change of CCF (between the definitive and proceeding tests) are highly correlated with clinical outcomes (p-values 1.36e-6 for level and 5.64e-10 for fold change, Kruskal-Wallis test). The CCFs of PD patients are an order of magnitude higher than the CCFs of SD and OR patients (median/mean 2.22%/8.96% for SD, 0.18/0.21% for PD, and 0.31/0.54% for OR; pairwise p-values 7.8e-6 for SD ~ PD, 2.7e-4 for OR ~ PD, and 7.0e-3 for SD ~ OR, Wilcoxon rank sum test). The fold change of CCF distinguishes the patient groups even better, which increases for PD, remains stable for SD, and decreases for OR patients (p-values 0.002, ~ 1, and 0.0001 respectively, Wilcoxon signed-rank test). Eleven drug-related mutations are identified from nine out of the 313 patients., Conclusions: The ctDNA fingerprint method improves both specificity and sensitivity of monitoring treatment response across several tumor types. It can identify tumor relapse/recurrence potentially earlier than imaging-based diagnosis. When augmented with tumor hotspot genes, it can track acquired drug-related mutations in patients.

Previous studies have indicated a correlation between nut intake and cancer risk in humans. This meta-analysis aimed to determine the relationship between nut consumption and the risks of cancer incidence and mortality. The PubMed, Embase, and Web of Science databases were searched up to August 2019. Relative risks and 95% confidence intervals were calculated using random-effects and fixed-effects models. We included 38 studies on nut consumption and cancer risk and 9 studies on cancer-specific mortality. Compared with no nut intake, nut intake was associated with a lower cancer risk (Relative Risk=0.90; 95% confidence interval, 0.86-0.94). Inverse associations were observed with colorectal cancer, gastric cancer, pancreatic cancer, and lung cancer in subgroup analyses. Tree nut consumption was found to reduce cancer risk (Relative Risk=0.88; 95% confidence interval, 0.79-0.99). Dose-response curves suggested that protective benefits against cancer increased with increased nut intake (P=0.005, P-nonlinearity=0.0414). An inverse correlation with cancer-specific mortality (Odd Ratio=0.90; 95% confidence interval, 0.88-0.92) was observed. In conclusion, nut consumption is inversely associated with the risks of cancer incidence and mortality; a higher intake is significantly associated with a lower cancer risk.

The prognostic value of long intergenic non-protein coding RNA 460 (LINC00460) overexpression in human solid malignant tumours remains unclear. Therefore, we conducted the meta-analysis to systematically review and assess the evidence for the correlation between LINC00460 overexpression and clinicopathological features and overall survival (OS) of patients with solid malignant tumour. An electronic search of PubMed, EMBASE, Web of Science, CNKI, Cochrane Library, Chinese Biological Medical Literature database and WanFang database was applied to select eligible articles. Pooled ORs or HRs with their 95% CIs were calculated to estimate the effects. 9 eligible studies with a total of 935 patients were enrolled in this meta-analysis. The results revealed that high LINC00460 expression was associated with positive lymph node metastasis (positive vs negative: OR=2.97, 95% CI 1.74 to 5.05, p=0.812), advanced tumour-node-metastasis stage (III+IV vs I+II: OR=2.82, 95% CI 1.64 to 4.85, p=0.193) and poorer differentiation (high vs low: OR=0.60, 95% CI 0.36 to 0.99, p=0.569). Additionally, the overexpression of LINC00460 could predict a poorer OS (HR=1.57, 95% CI 1.39 to 1.77) and the shorter disease-free survival (HR=2.32, 95% CI 1.25 to 4.31). Furthermore, according to subgroup analysis and meta-regression results, the heterogeneity of current meta-analysis may be attributed to the differences of cancer type and follow-up months. High expression of LINC00460 could predict poor prognosis in patients with solid malignant tumour. LINC00460 may serve as potential prognostic biomarker for clinical outcomes in various human solid malignant tumours., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Metabolomics is a powerful systems biology approach that monitors changes in biomolecule concentrations to diagnose and monitor health and disease. However, leading metabolomics technologies, such as NMR and mass spectrometry (MS), access only a small portion of the metabolome. Now an approach is presented that uses the high sensitivity and chemical specificity of surface-enhanced Raman scattering (SERS) for online detection of metabolites from tumor lysates following liquid chromatography (LC). The results demonstrate that this LC-SERS approach has metabolite detection capabilities comparable to the state-of-art LC-MS but suggest a selectivity for the detection of a different subset of metabolites. Analysis of replicate LC-SERS experiments exhibit reproducible metabolite patterns that can be converted into barcodes, which can differentiate different tumor models. Our work demonstrates the potential of LC-SERS technology for metabolomics-based diagnosis and treatment of cancer., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Long intergenic non-coding RNA 01296 (LINC01296) has been reported to play an important role in many human malignancies, but a consistent perspective has not been established now. To explore the prognostic value of LINC01296 in different types of human solid malignant tumours, we performed this meta-analysis.An electronic search of PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, Cochrane Library, Chinese Biological Medical Literature database and WanFang database was applied to select eligible literatures. Pooled ORs or HRs with their 95% CIs were calculated to estimate the effects.A total of 559 patients from nine eligible studies were enrolled in this meta-analysis. The results revealed that high LINC01296 expression was significantly related to larger tumour size (OR 3.42, 95% CI 2.08 to 5.63), lymph node metastasis (OR 3.03, 95% CI 2.01 to 4.57) and advanced tumor-node-metastasis (TNM) stage (OR 4.41, 95% CI 2.65 to 7.34). Moreover, we found that elevated LINC01296 expression predicted a poor outcome for overall survival (HR 1.78, 95% CI 1.48 to 2.14) and recurrence-free survival (HR 4.00, 95% CI 1.04 to 15.67).High expression levels of LINC01296 were associated with unfavourable clinical outcomes of patients with cancer. Our results indicated that LINC01296 could serve as a prognostic predictor in human solid malignant tumours., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: As an important downstream factor in the Hippo pathway, yes-associated protein 1(YAP1) has been detected to be elevated in various cancers and demonstrated to play a role in tumor development. Therefore, we evaluated by a meta-analysis the prognostic value of YAP1 in cancer patients., Results: Sixty-eight studies with 8631 patients were identified. The results indicated that YAP1 overexpression predicted unfavorable patient prognosis in studies with overall survival (OS) (HR=1.76, 95%CI: 1.50-2.06, p <0.001) and disease-free survival (DFS) (HR=1.39, 95%CI: 1.22-1.59, p <0.001), as well as in studies with recurrence-free survival (RFS) (HR=2.38, 95%CI: 1.73-3.27, p <0.001), and disease-specific survival (DSS) (HR=2.04, 95%CI: 1.55-2.70, p <0.001). Meanwhile, YAP1 overexpression was also observed to be significantly associated with worse OS in GEPIA (HR=1.2, p <0.001)., Conclusions: Overexpression of YAP1 showed great association with poorer prognosis in patients with various cancers, particularly liver cancer. Therefore, YAP1 might be an important prognostic marker and a novel target of cancer therapy., Methods: We searched for potential publications in several online databases and retrieved relevant data. Overall and subgroup analyses were performed. Begg's and Egger's tests were used to assess publication bias. Online dataset GEPIA was used to generate the survival curves and verify the prognostic role of YAP1 in patients with tumors.

Traditional cancer-therapeutic modalities such as chemotherapy suffer from the low therapeutic efficiency and severe side effects. The emerging nanocatalytic therapy could in-situ catalyze the endogenous substances into highly toxic species and then efficiently kill the cancer cells, but the lack of high-performance nanocatalysts hinders their broad clinical translation. In this work, we have successfully developed, for the first time, nanosized zero-valence crystalized iron nanoparticles for in-situ triggering nanocatalytic Fenton reaction within tumor microenvironment to produce large amounts of hydroxyl radicals and subsequently kill the cancer cells, which could be further synergistically enhanced by either photonic hyperthermia or magnetic hyperthermia as assisted by these iron nanoparticles acting as photothermal-conversion or magnetothermal-conversion nanoagents, respectively. Especially, the excellent magnetic performance of these zero-valence crystallized iron nanoparticles has achieved both in vitro and in vivo contrast-enhance magnetic resonance imaging for potentially guiding the photonic/magnetic hyperthermia-synergistic nanocatalytic cancer therapy. This work not only provides the new type of iron-based nanoparticles for biomedical application, but also demonstrates the high efficiency of nanocatalytic cancer therapy as assisted by both photonic and magnetic hyperthermia., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Tumor mutation burden (TMB), DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI), and PD-L1 amplification (PD-L1 AMP) may predict the efficacy of the PD-1/PD-L1 blockade. With the broadening landscape of immunotherapy use, it is important to identify patients who are likely to benefit from the therapy. This study aimed to characterize the distributions of these biomarkers and explore the relationships among these biomarkers for Chinese patients with cancer., Methods: In this study, we examined the aforementioned biomarkers in more than 1000 Chinese patients with cancer. These biomarkers were determined based on whole-exome sequencing (WES) of tumor/blood samples., Results: Of the 953 samples from Chinese cancer patients assessed in this study, 35% exhibited high TMB (TMB-H), 4% were positive for high MSI (MSI-H), dMMR occurred in 0.53%, and PD-L1 AMP was positive in 3.79%. We found higher rates of TMB-H among hepatocellular carcinoma, breast cancer, and esophageal cancer patients than was reported for The Cancer Genome Atlas (TCGA) data. Lung cancer patients with EGFR mutations had significantly lower TMB values than those with wild-type EGFR, and increased TMB was significantly associated with dMMR in colorectal cancer (CRC). The frequency of tumors with MSI-H was the highest in CRC and gastric cancer. PD-L1 AMP occurred most frequently in lung squamous cell carcinoma and HER2-positive breast cancer. While MSI and dMMR are associated with higher mutational loads, correlations between TMB-H and other biomarkers, between MSI-H and dMMR, and between PD-L1 AMP and other biomarkers were low, indicating different underlying causes of the four biomarkers., Conclusion: The results reveal the frequency of these biomarkers in different malignancies, with potential implications for PD-1/PD-L1 blockade use for Chinese patients with cancer., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The association between hyperuricemia or gout and cancer risk has been investigated in various published studies, but their results are conflicting. We conducted a meta-analysis to investigate whether hyperuricemia or gout was associated with the cancer incidence and mortality. Linear and nonlinear trend analyses were conducted to explore the dose-response association between them. The pooled relative risk (RR) and 95% confidence interval (CI) were used to evaluate cancer risk. A total of 24 articles (33 independent studies) were eligible for inclusion. When compared participants with the highest SUA (hyperuricemia) levels and those with the lowest SUA levels, the pooled RR was 1.08 (95% CI, 1.04-1.12), it was significantly associated among males but not among females (males, RR = 1.07; 95% CI, 1.03-1.11; females, RR = 1.06; 95% CI, 0.96-1.17). Hyperuricemia increased total cancer mortality (RR = 1.15; 95% CI, 1.05-1.26), but a significant association was observed in females rather than in males (females: RR = 1.26; 95% CI, 1.09-1.45; males, RR = 1.02; 95% CI, 0.80-1.30). Linear relationships of SUA levels with overall cancer incidence (p for nonlinearity = 0.238) and overall cancer mortality (p for nonlinearity = 0.263) were identified. However, 1 mg/dL increment in SUA levels was weakly significant in overall cancer incidence (RR = 1.01; 95% CI, 1.01-1.01) but not associated with overall cancer mortality (RR = 1.01; 95% CI, 0.99-1.03). Gout was significantly associated with increased cancer incidence (RR = 1.19; 95% CI, 1.12-1.25). In conclusion, Hyperuricemia or gout was associated with higher cancer incidence and mortality. Though a potential linear relationship between them was found, we'd better treat this result with caution., (© 2019 Wiley Periodicals, Inc.)

Roundabout4 (Robo4) is a transmembrane receptor that belongs to the Roundabout (Robo) family of axon guidance molecules. Robo4 is an endothelial-specific receptor that participates in endothelial cell migration, proliferation, and angiogenesis and the maintenance of vasculature homeostasis. The purpose of this review is to summarize and analyze three main mechanisms related to the expression and function of Robo4 during developmental and pathological angiogenesis. In this review, static shear stress and the binding of transcription factors such as E26 transformation-specific variant 2 (ETV2) and Slit3 induce Robo4 expression and activate Robo4 during tissue and organ development. Robo4 interacts with Slit2 or UNC5B to maintain vascular integrity, while a disturbed flow and the expression of transcription factors in inflammatory or neoplastic environments alter Robo4 expression levels, although these changes have uncertain functions. Based on the mechanisms described above, we discuss the aberrant expression of Robo4 in angiogenesis-related diseases and propose antiangiogenic therapies targeting the Robo4 signaling pathway for the treatment of ocular neovascularization lesions and tumors. Finally, although many problems related to Robo4 signaling pathways remain to be resolved, Robo4 is a promising and potentially valuable therapeutic target for treating pathological angiogenesis and developmental defects in angiogenesis., (© 2019 The Author(s).)

Aim: To evaluate whether clinical genomic sequencing may benefit Chinese patients with stage IV cancer. Patients & methods: Chinese patients with cancer and their oncologists were provided with genomic sequencing results and corresponding clinical treatment recommendations based on evidence-based medicine, defined as CWES (clinical whole-exome sequencing) analysis. Chinese patients with stage IV cancer who failed the previous treatment upon receiving the CWES reports were included for analyzing the impact of CWES on clinical outcomes in 1-year follow-ups. Results:  A total of 88.6% of 953 Chinese patients with cancer had clinically actionable somatic genomic alterations. Eleven patients followed the CWES reports, and 11 patients did not follow the CWES suggestions. The median progression-free survival of two groups were 12 and 4 months, and 45 and 91% of patients failed this round of therapy, respectively. Conclusion: The current study suggested that CWES has the potential to increase clinical benefits for Chinese patients with stage IV cancer.

Purpose: Stem-like cancer cells, with characteristic self-renewal abilities, remain highly refractory to various clinical interventions. As such, stemness-inhibiting entities, such as tumor suppressor p53, are therapeutically pursued for their anticancer activities. Interestingly, similar implications for tumor suppressor TAp73 in regulating stemness features within stem-like cancer cells remain unknown. Experimental Design: This study utilizes various in vitro molecular biology techniques, including immunoblotting, qRT-PCR, and mass spectrometry-based proteomics, and metabolomics approaches to study the role of TAp73 in human and murine embryonal carcinoma stem-like cells (ECSLC) as well as human breast cancer stem-like cells (BCSLC). These findings were confirmed using patient-derived brain tumor-initiating cells (BTIC) and in vivo xenograft models., Results: TAp73 inhibition decreases the expression of stem cell transcription factors Oct4, Nanog, and Sox-2, as well as tumorsphere formation capacity in ECSLCs. In vivo , TAp73-deficient ECSLCs and BCSLCs demonstrate decreased tumorigenic potential when xenografted in mice. Mechanistically, TAp73 modifies the proline regulatory axis through regulation of enzymes GLS, OAT , and PYCR1 involved in the interconversion of proline-glutamine-ornithine. Further, TAp73 deficiency exacerbates glutamine dependency, enhances accumulation of reactive oxygen species through reduced superoxide dismutase 1 (SOD1) expression, and promotes differentiation by arresting cell cycle and elevating autophagy. Most importantly, the knockdown of TAp73 in CD133 HI BTICs, separated from three different glioblastoma patients, strongly decreases the expression of prosurvival factors Sox-2, BMI-1, and SOD1, and profoundly decreases their self-renewal capacity as evidenced through their reduced tumorsphere formation ability., Conclusions: Collectively, we reveal a clinically relevant aspect of cancer cell growth and stemness regulation through TAp73-mediated redox-sensitive metabolic reprogramming., (©2018 American Association for Cancer Research.)

Significance: NAD + is an essential redox cofactor in cellular metabolism and has emerged as an important regulator of a wide spectrum of disease conditions, most notably, cancers. As such, various strategies targeting NAD + synthesis in cancers are in clinical trials. Recent Advances: Being a substrate required for the activity of various enzyme families, especially sirtuins and poly(adenosine diphosphate [ADP]-ribose) polymerases, NAD + -mediated signaling plays an important role in gene expression, calcium release, cell cycle progression, DNA repair, and cell proliferation. Many strategies exploring the potential of interfering with NAD + metabolism to sensitize cancer cells to achieve anticancer benefits are highly promising, and are being pursued., Critical Issues: With the multifaceted roles of NAD + in cancer, it is important to understand how cellular processes are reliant on NAD + . This review summarizes how NAD + metabolism regulates various pathophysiological processes in cancer, and how this knowledge can be exploited to devise effective anticancer therapies in clinical settings., Future Directions: In line with the redundant pathways that facilitate NAD + metabolism, further studies should comprehensively understand the roles of the various NAD + -synthesizing as well as NAD + -utilizing biomolecules to understand its true potential in cancer treatment.

Objective: Sorafenib, an oral vascular endothelial growth factor receptor tyrosine-kinase inhibitor, has become a cornerstone in the treatment of various malignancies. However, concerns have arisen regarding the risk of hemorrhage with sorafenib use. Nevertheless, the contribution of sorafenib to hemorrhage and the underlying risk factors remains unclear., Materials and Methods: We performed a meta-analysis to determine the incidence and risk of hemorrhage associated with sorafenib treatment. Multiple databases were searched to identify relevant studies. The analysis included randomized controlled trials (RCTs) that directly compared cancer patients treated with or without sorafenib. Statistical analyses were conducted to determine the overall incidence, relative risks (RRs), and 95% confidence intervals (CIs) using fixed- or random-effect models., Results: Ten RCTs involving 4720 patients were included in the analysis. Overall, the incidence rates of all- and high-grade hemorrhage in patients receiving sorafenib were 9.89% (95% CI: 8.73-11.18%) and 2.86% (95% CI: 2.25-3.63%), respectively. Sorafenib treatment increased the risk of all-grade hemorrhage in patients compared to control treatment (RR: 1.99; 95% CI: 1.59-2.49; P < 0.00001), but did not increase the incidence of high-grade hemorrhage (RR: 1.42; 95% CI: 0.95-2.12; P = 0.09). Subgroup analysis showed no significant increase in the risk of hemorrhage between patients with various malignancies or concurrent treatment. No evidence of publication bias was observed., Conclusion: In patients with malignancy, sorafenib treatment combined with standard treatment significantly increases the risk of low-grade hemorrhagic events., Competing Interests: None