Spatial Tuning of Light-Matter Interaction via Strain-Gradient-Induced Polarization in Freestanding Wrinkled 2D Materials.

To date, controlled deformation of two-dimensional (2D) materials has been extensively demonstrated with substrate-supported structures. However, interfacial effects arising from these supporting materials may suppress or alter the unique behavior of the deformed 2D materials. To address interfacial effects, we report, for the first time, the formation of a micrometer-scale freestanding wrinkled structure of 2D material without any encapsulation layers where we observed the enhanced light-matter interactions with a spatial modulation. Freestanding wrinkled monolayer WSe2 exhibited about a 330% enhancement relative to supported wrinkled WSe2 quantified through photoinduced force microscopy. Spatial modulation and enhancement of light interaction in the freestanding wrinkled structures are attributed to the enhanced strain-gradient effect (i.e., out-of-plane polarization) enabled by removing the constraining support and proximate dielectrics. Our findings offer an additional degree of freedom to modulate the out-of-plane polarization and enhance the out-of-plane light-matter interaction in 2D materials.

Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors.

Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cellular therapy by harvesting infiltrated lymphocytes from tumors, culturing and amplifying them in vitro and then infusing back to treat patients. Its diverse TCR clonality, superior tumor-homing ability, and low off-target toxicity endow TIL therapy unique advantages in treating solid tumors compared with other adoptive cellular therapies. Nevertheless, the successful application of TIL therapy currently is still limited to several types of tumors. Herein in this review, we summarize the fundamental work in the field of TIL therapy and the current landscape and advances of TIL clinical trials worldwide. Moreover, the limitations of the current TIL regimen have been discussed and the opportunities and challenges in the development of next-generation TIL are highlighted. Finally, the future directions of TIL therapy towards a broader clinical application have been proposed.

Social Anxiety and Mental Health Service Use Among Asian American High School Students.

Asian American adults endorse more symptoms of social anxiety (SA) on self-report measures than European Americans, but demonstrate lower prevalence rates of SA disorder in epidemiological studies. These divergent results create ambiguity concerning the mental health needs of Asian Americans. The present study is the first to investigate this issue in adolescents through assessment of self-reported SA in Asian American high school students. Parent and self-ratings of impairment related to SA and self-reported mental health service use for SA were also measured. Asian American students endorsed a greater number of SA symptoms and scored in the clinical range more frequently than other ethnic groups. Also, Asian American and Latino students endorsed more school impairment related to SA than other ethnic groups. No differences in parent-reported impairment or service utilization were identified. Implications for future research and treatment for SA among Asian American adolescents are discussed.

First report: PLATFORM study for precision treatment of rare tumors in China.

The purpose of this study was to present the preliminary results of the PLATFORM Study, which aimed to evaluate the effectiveness of precision treatment for rare tumors in China. This study involved a phase II, open-label, non-randomized, multi-arm, single-center clinical trial. Patients with advanced rare solid tumors, who had not responded to standard treatment, were enrolled. The primary objective was to assess the safety and efficacy of targeted therapies in patients with actionable genetic alterations and immune checkpoint inhibitors in patients lacking actionable genetic alterations. Out of the 922 cases screened, 107 patients underwent mutation detection, with a final enrollment of 64 cases for the study. Among these, 26 cases received targeted therapy, and 38 cases underwent immunotherapy. The study encompassed over 40 types of rare tumors. The overall objective response rate (ORR) was 7.0%, with a disease control rate (DCR) of 70%. Targeted therapy showed a higher ORR of 17.8% and a DCR of 100%. The median progression-free survival (PFS) was 4 months overall, with targeted therapy showing a median PFS of 5 months and immunotherapy showing a median PFS of 3 months. In conclusion, from this preliminary analysis, targeted therapy within the precision medicine framework demonstrated promising therapeutic potential for rare tumors. However, monotherapy immunotherapy exhibited limited efficacy, highlighting the challenges in overcoming tumor-specific variations. These findings underscore the importance of further research and the exploration of combination therapies to improve outcomes for patients with rare tumors.

Pan-cancer analysis of polo-like kinase family genes reveals polo-like kinase 1 as a novel oncogene in kidney renal papillary cell carcinoma.

Background: Polo-like kinases (PLKs) are a kinase class of serine/threonine with five members that play crucial roles in cell cycle regulation. However, their biological functions, regulation, and expression remain unclear. This study revealed the molecular properties, oncogenic role, and clinical significance of PLK genes in pan-cancers, particularly in kidney renal papillary cell carcinoma (KIRP). Methods: We evaluated the mutation landscape, expression level, and prognostic values of PLK genes using bioinformatics analyses and explored the association between the expression level of PLK genes and tumor microenvironment (TME), immune subtype, cancer immunotherapy, tumor stemness, and drug sensitivity. Finally, we verified the prognostic value in patients with KIRP through univariate and multivariate analyses and nomogram construction. Results: PLK genes are extensively altered in pan-cancer, which may contribute to tumorigenesis. These genes are aberrantly expressed in some types of cancer, with PLK1 being overexpressed in 31 cancers. PLK expression is closely associated with the prognosis of various cancers. The expression level of PLK genes is related with sensitivity to diverse drugs and cancer immunity as well as cancer immunotherapy. Importantly, we verified that PLK1 was overexpressed in KIRP tissues and could be an unfavorable prognostic biomarker in patients with KIRP. Hence, PLK1 may serve as an oncogenic gene in KIRP and should be explored in future studies. Conclusions: Our study comprehensively reports the molecular characteristics and biological functions of PLK family gens across human cancers and recommends further investigation of these genes as potential biomarkers and therapeutic targets, especially in KIRP.

Exosome-based anticancer vaccines: From Bench to bedside.

Exosomes, a subset of extracellular vesicles, are released by all active cells and play a crucial role in intercellular communications. Exosomes could facilitate the transfer of various biologically active molecules, such as DNA, non-coding RNAs, and proteins, from donor to recipient cells, thereby participating in diverse biological and pathological processes. Besides, exosomes possess unique characteristics, including non-toxicity, low-immunogenicity, and stability within biological systems, rendering them highly advantageous for cancer drug development. Meanwhile, accumulating evidence suggests that exosomes originating from tumor cells and immune cells possess distinct composition profiles that play a direct role in anticancer immunotherapy. Of note, exosomes can transport their contents to specific cells, thereby exerting an impact on the phenotype and immune-regulatory functions of targeted cells. Therapeutic cancer vaccines, an emerging therapeutics of immunotherapy, could enhance antitumor immune responses by delivering a large number of tumor antigens, thereby augmenting the immune response against tumor cells. Therefore, the therapeutic rationale of cancer vaccines and exosome-based immunotherapy are almost similar to some extent, but some challenges have hindered their application in the clinical setting. Here, in this review, we first summarized the biogenesis, structure, compositions, and biological functions of exosomes. Then we described the roles of exosomes in cancer biology, particularly in tumor immunity. We also comprehensively reviewed current exosome-based anticancer vaccine development and we divided them into three types. Finally, we give some insights into clinical translation and clinical trial progress of exosome-based anticancer vaccines for future direction.

Toward a comprehensive solution for treating solid tumors using T-cell receptor therapy: A review.

T-cell receptor therapy (TCR-T) has demonstrated efficacy, durability, and safety advantages in certain solid tumors (such as human papillomavirus-related tumors, synovial sarcoma, and melanoma). This study aimed to provide careful considerations for developing TCR-T for solid tumors. Therefore, in this review, we have summarized the current clinical application, advantage of TCR-T modalities and explored efficacy/safety-related parameters, particularly avidity, pharmacokinetics/pharmacodynamics, and indications, for solid tumors. Furthermore, we have investigated critical factors related to avidity, including antigen selection, T-cell receptor acquisition, optimization, and co-receptor engagement. Moreover, we have re-examined the expression of tumor antigens for a potentially higher coverage rate of solid tumors based on the current RNA-seq datasets. Finally, we have discussed the current limitations and future directions of TCR-Ts.

Nanoparticle drug delivery system for the treatment of brain tumors: Breaching the blood-brain barrier.

The current status of clinical trials utilizing nanoparticle drug delivery system (NDDS) for brain tumors was summarized.Image 1.

HLA and tumour immunology: immune escape, immunotherapy and immune-related adverse events.

PURPOSE: As molecules responsible for presenting antigens to T lymphocytes, leukocytes antigens (HLAs) play a vital role in cancer immunology. This review aims to provide current understanding of HLAs in tumour immunology. METHODS: Perspectives on how HLA alterations may contribute to the immune escape of cancer cells and resistance to immunotherapy, and potential methods to overcome HLA defects were summarized. In addition, we discussed the potential association between HLA and immune-related adverse events (irAEs), which has not been reviewed elsewhere. RESULTS: Downregulation, loss of heterogeneity and entire loss of HLAs are responsible for the immune escape of tumour cells. The strategies to overcome the HLA defects can be effective therapies of cancer. Compared with classical HLA-I, non-classical HLA-I molecules, such as HLA-E and HLA-G, appear to be more reliable predictors of prognosis, as they tend to play immunosuppressive roles in antitumor response. Relative diversified or high expression of classical HLA-I are potential predictors of favourable response of immunotherapy. Certain HLA types may be associated to enhanced affinity to self-antigen-mimicked tumour-antigens, thus may positively correlated to irAEs triggered by checkpoint inhibitors. CONCLUSIONS: Further studies exploring the relationship between HLAs and cancer may not only lead to the development of novel therapies but also bring about better management of irAEs.

Drug conjugate-based anticancer therapy - Current status and perspectives.

Drug conjugates are conjugates comprising a tumor-homing carrier tethered to a cytotoxic agent via a linker that are designed to deliver an ultra-toxic payload directly to the target cancer cells. This strategy has been successfully used to increase the therapeutic efficacy of cytotoxic agents and reduce their toxic side effects. Drug conjugates are being developed worldwide, with the potential to revolutionize current cancer treatment strategies. Antibody-drug conjugates (ADCs) have developed rapidly, and 14 of them have received market approval since the first approval event by the Food and Drug Administration in 2000. However, there are some limitations in the use of antibodies as carriers. Other classes of drug conjugates are emerging, such as targeted drugs conjugated with peptides (peptide-drug conjugates, PDCs) and polymers (polymer-drug conjugates, PolyDCs) with the remaining constructs similar to those of ADCs. These novel drug conjugates are gaining attention because they overcome the limitations of ADCs. This review summarizes the current state and advancements in knowledge regarding the design, constructs, and clinical efficacy of different drug conjugates.

Rare tumors: a blue ocean of investigation.

Advances in novel drugs, therapies, and genetic techniques have revolutionized the diagnosis and treatment of cancers, substantially improving cancer patients' prognosis. Although rare tumors account for a non-negligible number, the practice of precision medicine and development of novel therapies are largely hampered by many obstacles. Their low incidence and drastic regional disparities result in the difficulty of informative evidence-based diagnosis and subtyping. Sample exhaustion due to difficulty in diagnosis also leads to a lack of recommended therapeutic strategies in clinical guidelines, insufficient biomarkers for prognosis/efficacy, and inability to identify potential novel therapies in clinical trials. Herein, by reviewing the epidemiological data of Chinese solid tumors and publications defining rare tumors in other areas, we proposed a definition of rare tumor in China, including 515 tumor types with incidences of less than 2.5/100 000 per year. We also summarized the current diagnosis process, treatment recommendations, and global developmental progress of targeted drugs and immunotherapy agents on the status quo. Lastly, we pinpointed the current recommendation chance for patients with rare tumors to be involved in a clinical trial by NCCN. With this informative report, we aimed to raise awareness on the importance of rare tumor investigations and guarantee a bright future for rare tumor patients.

Targeting rare tumors: new focus for clinical research in China.

Rare tumor has a huge unmet medical need without standard regimens, calling for novel therapeutic interventions. The National Cancer Center of China identified a threshold of incidence for rare tumor as 2.5/100,000, based on the characteristics of Chinese population. Molecular profiles for rare tumor patients in China further provided prospects for precise and individualized targeted treatment. An ongoing phase II clinical trial, the PLATFORM study, is the first trial tailored for rare solid tumors in China, featured by molecule-guided therapeutics. With the promulgation of supportive policies to encourage the development of innovative drugs for rare tumors in China, opportunities will be provided for these patients and the gap will be filled in the treatment of rare tumors.

The reliability and integrity of overall survival data based on follow-up records only and potential solutions to the challenges.

Overall survival (OS) is considered the standard clinical endpoint to support effectiveness claims in new drug applications globally, particularly for lethal conditions such as cancer. However, the source and reliability of OS in the setting of clinical trials have seldom been doubted and discussed. This study first raised the common issue that data integrity and reliability are doubtful when we collect OS information or other time-to-event endpoints based solely on simple follow-up records by investigators without supporting material, especially since the 2019 COVID-19 pandemic. Then, two rounds of discussions with 30 Chinese experts were held and 12 potential source scenarios of three methods for obtaining the time of death of participants, including death certificate, death record and follow-up record, were sorted out and analysed. With a comprehensive assessment of the 12 scenarios by legitimacy, data reliability, data acquisition efficiency, difficulty of data acquisition, and coverage of participants, both short-term and long-term recommended sources, overall strategies and detailed measures for improving the integrity and reliability of death date are presented. In the short term, we suggest integrated sources such as public security systems made available to drug inspection centres appropriately as soon as possible to strengthen supervision. Death certificates provided by participants' family members and detailed standard follow-up records are recommended to investigators as the two channels of mutual compensation, and the acquisition of supporting materials is encouraged as long as it is not prohibited legally. Moreover, we expect that the sharing of electronic medical records and the legal disclosure of death records in established health registries can be realized with the joint efforts of the whole industry in the long-term. The above proposed solutions are mainly based on the context of China and can also provide reference for other countries in the world.

Clinical Investigations of CAR-T Cell Therapy for Solid Tumors.

Cell therapy is a distinguished targeted immunotherapy with great potential to treat solid tumors in the new era of cancer treatment. Cell therapy products include genetically engineered cell products and non-genetically engineered cell products. Several recent cell therapies, especially chimeric antigen receptor (CAR)-T cell therapies, have been approved as novel treatment strategies for cancer. Many clinical trials on cell therapies, in the form of cell therapy alone or in combination with other treatments, in solid tumors, have been conducted or ongoing. However, there are still challenges since adverse events and the limited efficacy of cell therapies have also been observed. Here, we concisely summarize the clinical milestones of the conducted and ongoing clinical trials of cell therapy, introduce the evolution of CARs, discuss the challenges and limitations of these therapeutic modalities taking CAR-T as the main focus, and analyze the disparities in the regulatory policies in different countries.

CEA-regulated Oncolytic Virus Anticancer Therapy: A Promising Strategy for Rare Solid Tumors.

BACKGROUND: Rare solid tumors have attracted much more attention due to the great unmet clinical need, limited treatment options, and poor prognosis. As the most thoroughly studied tumor marker, carcinoembryonic antigen (CEA) can not only overexpress in various common solid tumors but also in several rare solid tumors. Oncolytic virus therapy has achieved excellent anticancer effects in the past decades. Due to the specific high expression of CEA in certain tumor tissues but not in normal tissues, CEA has been applied to improve the tumor specificity of gene expression. METHODS: The studies of CEA expression in rare solid tumors and CEA-regulated oncolytic virus therapy were reviewed. RESULTS: We showed the types of rare solid tumors with the overexpression of CEA. Elevated serum CEA levels can indicate the diagnosis, response of surgery or system therapy, distal metastasis, recurrence, and survival. Due to high tumor specificity, CEA-regulated OA therapy has demonstrated a surprising antitumor effect for common CEA-positive tumors in preclinical trials. CONCLUSION: These data suggested that CEA could be a diagnostic and prognostic biomarker for several rare solid tumors. We proposed the hypothesis that CEA-regulated oncolytic virus therapy could be a promising therapeutic strategy for CEA-positive rare solid tumors.

An overview of cancer drugs approved through expedited approval programs and orphan medicine designation globally between 2011 and 2020.

The use of expedited approval pathways for anticancer drug development, which provide the advantages of high efficiency and cost-effectiveness, has expanded significantly in recent years. During the past decade, a total of 410 new molecular entities have been approved by the US Food and Drug Administration (FDA), with a steady growth of 6.5% in the US. In Europe, 9-75% of approved anticancer drugs were granted at least one expedited approval program. Various expedited pathways have also been implemented worldwide to address underrepresented medical needs rapidly. China has adapted several expedited approval programs, including breakthrough therapy designation, priority review, and conditional approval, to keep up with the growth in pharmaceutical development. It is expected that worldwide standards for drug approval will become more standardized in the next decade.

KRAS Mutation in Rare Tumors: A Landscape Analysis of 3453 Chinese Patients.

KRAS is the most commonly mutated oncogene in human cancers. Targeted therapy and immunotherapy for this gene have made remarkable progress in recent years. However, comprehensive molecular landscape analysis of KRAS in rare tumors is lacking. Retrospective analysis was performed on clinical samples from patients with rare tumors collected between September 2015 and September 2021, using hybrid-capture-based next-generation sequencing for genomic profiling and immunohistochemistry assay for PD-L1. Of the 3,453 patients included in analysis, KRAS mutations were identified in 8.7% patients in overall; mutation rate and mutation subtypes varied widely across tumor systems and subtypes. KRAS mutations included 21 missense mutations, of which G12D (29.2%), G12V (24.6%), and G13D (10.8%) were most common. Interestingly, KRAS G12C was observed in 0.6% patients overall, and in 5.7% of sarcomatoid carcinoma of the lung and 5.4% of clear cell ovarian cancer tumors, but none in small-bowel cancer tumors. 31.8% KRAS mutations and 36.4% KRAS G12C mutations co-occurred with other targetable alterations. No significant correlation was observed between TMB-H, MSI-H, PD-L1 status, and KRAS mutation status, which may be related to the high proportion of G12D. This study is the first KRAS mutation landscape study in rare tumors of large sample size in China and worldwide. Our results suggest that targeted therapy and immunotherapy are both feasible, albeit complex, in these patients. This information may have significant impact on the operation of clinical trials for rare tumor patients with KRAS mutations in China.