Different Types Of Malignancies Research Articles

Methyl-CpG binding domain protein 2 (Mbd2) drives breast cancer progression through the modulation of epithelial-to-mesenchymal transition.

Methyl-CpG-binding domain protein 2 (Mbd2), a reader of DNA methylation, has been implicated in different types of malignancies, including breast cancer. However, the exact role of Mbd2 in various stages of breast cancer growth and progression in vivo has not been determined. To test whether Mbd2 plays a causal role in mammary tumor growth and metastasis, we performed genetic knockout (KO) of Mbd2 in MMTV-PyMT transgenic mice and compared mammary tumor progression kinetics between the wild-type (PyMT-Mbd2+/+) and KO (PyMT-Mbd2-/-) groups. Our results demonstrated that deletion of Mbd2 in PyMT mice impedes primary tumor growth and lung metastasis at the experimental endpoint (postnatal week 20). Transcriptomic and proteomic analyses of primary tumors revealed that Mbd2 deletion abrogates the expression of several key determinants involved in epithelial-to-mesenchymal transition, such as neural cadherin (N-cadherin) and osteopontin. Importantly, loss of the Mbd2 gene impairs the activation of the PI3K/AKT pathway, which is required for PyMT-mediated oncogenic transformation, growth, and survival of breast tumor cells. Taken together, the results of this study provide a rationale for further development of epigenetic therapies targeting Mbd2 to inhibit the progression of breast cancer.

A comprehensive analysis of the prognostic and immunological role of ANK3 in pan-cancer.

Cancer is a common cause of death around the world. Immunotherapy plays a significant role in cancer treatment but still has limitations. The ankyrin-3 (ANK3) gene has been shown to have a variety of biological roles and has also been shown to be closely linked to individual cancers. We systematically investigated the role of ANK3 in pan-cancer, particularly in relation to immunity. We collected data from a number of databases, including the The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), tumor-immune system interactions (TISIDB), cBioPortal, Tumor Immune Estimation Resource (TIMER), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), BioGRID, and SangerBox databases. R (version 3.6.3) was used for the statistical analysis and data visualization. The expression of ANK3 in tumors and its effects on patient prognosis, immune infiltration, neoantigens, the microenvironment, immune checkpoints (ICs), the tumor mutation burden, microsatellite instability (MSI), methylation, mismatch repair (MMR) genes, and cancer-associated fibroblasts were investigated. A gene set enrichment analysis (GSEA) was also conducted. The ANK3 gene was differentially expressed at the messenger RNA (mRNA) and protein levels in various human tumors. The prognosis of patients with different types of malignancies was correlated with the level of ANK3 expression. The immunological microenvironment was also linked to ANK3 expression, especially in colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), and liver hepatocellular carcinoma (LIHC). ANK3 was also associated with ICs, immune neoantigens, MSI, the tumor mutation load, MMR genes, and DNA methylation. Finally, we found the key pathway related to the ANK3 gene through the enrichment analysis. ANK3 could serve as a new biomarker specific to prognosis and immunotherapy in various cancers. Our findings could contribute to the development of novel strategies for treating malignancies.

Modulation of cancer progression by circRNA/ NF-kB axis

The newest class of noncoding RNAs with distinctive characteristics is called circular RNAs (circRNAs). These novel RNAs are more stable than other RNAs because they lack 5’ and 3’ ends, instead having their two ends created from pre-mRNA through a process called back-splicing. They are also widely expressed in a variety of species, including viruses, plants, and mammals. There is growing evidence that circRNAs are enriched in the NF-κB pathway. The development of many types of malignancies is associated with aberrant activation of the NF-κB pathway. Recent findings indicate that the circRNA/NF-κB axis controls the expression of genes linked to cancer and, consequently, the growth of tumors. Moreover, circRNAs might interact with the NF-κB pathway to affect biological processes of cells. A comprehensive understanding of the molecular processes behind the involvement of circRNA linked to the NF-κB pathway in the progression of distinct malignancies would provide novel opportunities for cancer therapy. Therefore, this article will briefly discuss the function of circRNAs and the NFκB pathway in cancer. Next, it will address the crucial role that circRNAs associated with NF-κB play in the progression of different types of malignancies.

Epidemiology of a Hospital-Based Pediatric Cancer Registry - An Experience at a Major Tertiary Care Center in Pakistan

Background: Cancer is a prominent non-communicable disease, responsible for more than 8 million deaths each year worldwide. Globally, 400,000 children and daily 1000 children are diagnosed with cancer. Objective: The current study aims to analyze retrospective childhood cancer registry data from IHHN since 2016 and provide the Age Standardized Incidence Rates (ASIR) for children having different types of malignancies. Method: A retrospective study was conducted through a chart review of the childhood cancer registry, data retrieved from the Indus Paediatric Oncology Database (IPOD) software. Only patients with behavior code/3 for positive malignancy, as defined in the International Classification of Disease for Oncology, 3rd edition (ICD-O-3) were included in the dataset. Results: A total of 4631 children diagnosed with cancer were enrolled, with 2951 (63.7%) males and 1680 (36.3%) females. Overall median age and Interquartile range were 7(3.3-11) years. Leukemia was the predominant cancer in both genders, the second highest being lymphoma. Central Nervous System (CNS) tumors were the third highest cancer in males and soft tissue sarcomas in females. Hepatic tumors are the least common among genders. Conclusion: In conclusion, the childhood cancer registry at the Indus Hospital and Health Network (IHHN) reported standard quality data including patients mostly from Sindh and Baluchistan along with other provinces and neighboring countries. Moreover, at the national level, there is an essential need for the formulation of an effective childhood cancer registration system by policymakers to determine the true incidence rate and etiology of common cancers.

A Machine Learning-Based Unenhanced Radiomics Approach to Distinguishing Between Benign and Malignant Breast Lesions Using T2-Weighted and Diffusion-Weighted MRI.

Breast MRI has been recommended as supplemental screening tool to mammography and breast ultrasound of breast cancer by international guidelines, but its long examination time and use of contrast material remains concerning. To develop an unenhanced radiomics model with using non-gadolinium based sequences for detecting breast cancer based on T2-weighted (T2W) and diffusion-weighted (DW) MRI. Retrospective analysis followed by retrospective and prospective cohorts study. 1760 patients: Of these, 1293 for model construction (n = 775 for training and 518 for validation). The remaining patients for model testing in internal retrospective (n = 167), internal prospective (n = 188), and external retrospective (n = 112) cohorts. 3.0T MR scanners from two institution. T2WI, DWI, and first contrast-enhanced T1-weighted sequence. AUCs in distinguishing breast cancer were compared between combined model with gadolinium agent sequence and unenhanced model. Subsequently, the AUCs in testing cohorts of unenhanced model was compared with two radiologists' diagnosis for this research. Finally, patient subgroup analysis in testing cohorts was performed based on clinical subgroups and different types of malignancies. Mann-Whitney U test, Kruskal-Wallis H test, chi-square test, weighted kappa test, and DeLong's test. The unenhanced radiomics model performed best under Gaussian process (GP) classifiers (AUC: training, 0.893; validation, 0.848) compared to support vector machine (SVM) and logistic, showing favorable prediction in testing cohorts (AUCs, 0.818-0.840). The AUCs for the unenhanced radiomics model were not statistically different in five cohorts from those of the combined radiomics model (P, 0.317-0.816), as well as the two radiologists (P, 0.181-0.918). The unenhanced radiomics model was least successful in identifying ductal carcinoma in situ, whereas did not show statistical significance in other subgroups. An unenhanced radiomics model based on T2WI and DWI has comparable diagnostic accuracy to the combined model using the gadolinium agent. 4 TECHNICAL EFFICACY: Stage 2.

Prognostic Value of C-reactive Protein-to-albumin Ratio after Curative Resection in Patients with Colorectal Cancer.

The current retrospective study aimed to evaluate the association between combined preoperative and postoperative C-reactive protein-to-albumin ratio, which is correlated with prognosis in different types of malignancies, and prognosis after curative resection in patients with colorectal cancer. This study enrolled 263 patients who underwent curative resection for stage II/III colorectal cancer. C-reactive protein-to-albumin ratio was calculated within 30 days before and 7 days after surgery. Receiver operating characteristic curve analyses were performed to determine the optimal cutoff values of preoperative and postoperative C-reactive protein-to-albumin ratio. The correlations between combined preoperative and postoperative C-reactive protein-to-albumin ratio and prognosis were analyzed. The cutoff values of preoperative and postoperative C-reactive protein-to-albumin ratio were 0.223 and 0.813, respectively; higher ratios were significantly associated with poor overall survival, based on the Kaplan-Meier curves (p < 0.001, p = 0.003, respectively). Further, preoperative and postoperative C-reactive protein-to-albumin ratios were correlated with poor progression-free survival (p < 0.001, p = 0.064, respectively). In the multivariate analysis, combined preoperative and postoperative C-reactive protein-to-albumin ratio was an independent predictor of overall survival and progression-free survival (p = 0.012, p = 0.044, respectively). Compared with low preoperative and postoperative C-reactive protein-to-albumin ratio, high ratios of that were significantly associated with poor overall survival (hazard ratio = 3.897, p = 0.006) and progression-free survival (hazard ratio = 2.130, p = 0.029). Combined preoperative and postoperative C-reactive protein-to-albumin ratio, useful for prognostic prediction, can be a promising prognostic marker after curative resection in patients with colorectal cancer.

Donor-derived myeloid sarcoma in a kidney transplant recipient: clinical case study and relevance of a multidisciplinary approach in therapy and diagnosis

Background. Malignant tumors are one of the main causes of unfavorable outcomes in solid organ transplant recipients in the long term after transplantation. Localization of these tumors in a transplanted organ may cause loss of graft function. After chronic graft dysfunction and infections, malignant neoplasms come next as one of the leading causes of late kidney graft loss. The incidence of different types of malignancies varies according to the transplanted organ. Knowledge of etiology, pathogenesis, peculiarities of diagnosis and treatment of malignant tumors in solid organ transplant recipients is a significant part of screening at any stage of post-transplant period. Late diagnosis of malignancies in a transplanted kidney amidst disconnected stages of treatment and follow-up leads not only to graft loss, but also jeopardizes the life of recipients.Clinical case description. The patient is a 29-year-old female. History: IgA nephropathy with nephrosclerosis. Renal replacement therapy (RRT) with long-term hemodialysis since March 2019. Kidney transplantation from a deceased donor to the right external iliac vessels on March 13, 2019. Graft function is immediate. In October 2020, a tumor in the transplanted kidney was detected for the first time. In November 2021, an emergency graft nephrectomy was performed for health reasons. Antibacterial, antifungal therapy was carried out. Results of morphological study of the removed renal graft with immunohistochemistry (IHC) were obtained. The structure and phenotype of the tumor are consistent with myeloid sarcoma. Trephine biopsy: normocellular bone marrow.Conclusion. The 29-year-old patient was diagnosed with donor-derived myeloid sarcoma in her kidney transplant with the development of paraneoplastic syndrome and multi-organ failure. Currently, the patient is receiving RRT by long-term scheduled hemodialysis. Organ recipients need to be managed by a multidisciplinary team of specialized and highly specialized specialists, taking into account comorbid status and features of the course of the underlying disease.

Molecular Epidemiology and Associated Risk Factors of Parasites in Oral Cavity of Children with Malignancies in Western Iran.

This survey was designed to study the molecular epidemiology and risk factors of Entamoeba gingivalis and Trichomonas tenax in children with underlying malignancies and those on chemotherapy in Lorestan province, West of Iran. The present cross-sectional descriptive study was performed on children who suffering from different types of malignancies or receiving treatment by chemotherapy referring to oncology section of hospitals of Lorestan Province, Iran during May 2021 to April 2022. The frequency of oral cavity protozoa was investigated using microscopic and conventional polymerase chain reaction (PCR). E. gingivalis and T. tenax parasites were found in 23 (25.5%) by microscopic method and 28 (31.1%) using PCR in children with malignancy. Among positive samples, 20 (71.4%) were infected with E. gingivalis; whereas 8 (28.6%) of the participants were positive for T. tenax. In the multivariate model, living in rural regions (OR= 3.437; 95% CI= 1.22-9.63; p=0.019) and using mouthwash (OR= 0.082; 95% CI= 0.018-0.37; p<0.001) were significantly related with the frequency of oral cavity parasites. Our results showed the high frequency of oral cavity parasites in children who suffering malignancies or receiving treatment by chemotherapy in Lorestan province, Iran. The awareness of the main risk factors for oral cavity parasites particularly using mouthwash is necessary in improving public and oral health strategies in children with cancer. Consequently, oncologist and dental practitioners must be aware to identify and manage oral health concerns in in children who suffering from different types of malignancies to prevent the oral diseases and infections.

Safety Profile of Combination Treatment with Radiotherapy and Immune Checkpoint Blockades: A Multi-Institute Real World Experience

Immune checkpoint blockades have become widely used in recent years and have been approved as standard first-line and subsequent treatment for different types of malignancy. Combination treatment with irradiation also showed promising results in previous clinical studies. However, the treatment toxicities of this combination strategy have not been well defined. We hypothesized combination therapy does not add additional toxicities to immune checkpoint blockade alone. The study aims to investigate the safety profile of combination treatment with immune checkpoint blockade and radiotherapy in all type cancer patients. We conducted a population-based retrospective cohort study using the electronic medical records from three hospitals in Taiwan from January 01, 2015, to December 31, 2020. Baseline demographic data, laboratory examination, and treatment history were collected. Patients with radiotherapy exposure and immune checkpoint blockade were enrolled. The primary endpoint was all grade toxicities. All patients were monitored from the date of initiating immune checkpoint blockade or irradiation until the event of death, loss follow-up, or any defined adverse events. All data was managed using SAS v.9.4 software. Kaplan-Meier estimators and cox proportional hazard regression models were used to compute the safety profile of combination treatment. The statistical significance was considered with a p-value <0.05. A total of 305 cases, including 181 male patients and 124 female patients, received combination treatment with immune checkpoint blockade and radiotherapy with different time sequences. The most common cancer types are lung cancer (33.1%) followed by gastroesophageal cancer (16.7%) and hepatobiliary cancer (13.8%). The most common toxicities were arthralgia (25.9%), followed by enterocolitis (23.6%), and anemia (21%). 11 cases (3.6%) developed pneumonitis, 5 cases (1.6%) developed myocarditis, and 5 cases (1.6%) developed hepatitis during combination treatment. There is no evidence leads to additional toxicities based on current real-world experience. Severe immune related adverse events were not increased with this combination strategy compared to historical data. This warrant further prospective analysis.

Inferior vena cava tumor thrombus: clinical outcomes at a canadian tertiary center.

This study reports the surgical management and outcomes of patients with malignancies affecting the IVC. This was a retrospective study that considered patients undergoing surgery for IVC thrombectomy in Calgary, Canada, from 1 January 2010 to 31 December 2021. Parameters of interest included primary malignancy, the extent of IVC involvement, surgical strategy, and medium-term outcomes. Six patients underwent surgical intervention for malignancies that affected the IVC. One patient had a retroperitoneal leiomyosarcoma, 1 had hepatocellular carcinoma with thrombus extending into the IVC and right atrium, 1 had adrenocortical carcinoma with IVC thrombus extending into the right atrium, and 3 had clear cell renal cell carcinoma with thrombus extending into the IVC. Surgical strategy for the IVC thrombectomy varied where 5 patients required the institution of cardiopulmonary bypass and underwent deep hypothermic circulatory arrest. No patient died perioperatively. One patient died 15-months post-operatively from aggressive malignancy. Different types of malignancy can affect the IVC and surgical intervention is usually indicated for these patients. Herein, we have reported the outcomes of IVC thrombectomy at our center.

The study of long noncoding RNA TUG 1 and ZEB2-AS1 expression in newly diagnosed Egyptian adult acute myeloid leukemia patients

BackgroundThe hematopoietic malignancy acute myeloid leukemia is a fatal disease with poor clinical prognoses. Long non-coding RNA taurine-upregulated gene1 (lncRNA TUG1) and zinc finger E-box binding homeobox 2 antisense RNA1 (lncRNA ZEB2-AS1) are reported to participate in the development and progression of different types of malignancies. The goal of the current study was to evaluate the prognostic value of the lncRNAs TUG1 and ZEB2-AS1 as well as their various expression patterns in newly diagnosed Egyptian adult acute myeloid leukemia patients.MethodsWe assessed the expression levels of both lncRNA TUG1 and lncRNA ZEB2-AS1 using the quantitative real-time reverse transcription polymerase chain reaction technique (qRT-PCR) in 80 newly diagnosed AML patients and 20 healthy subjects.ResultslncRNA TUG1 expression was significantly higher in the AML cases compared to the controls (P < 0.001), whereas lncRNA ZEB2-AS1 expression was considerably lower in the AML cases in comparison with the controls (P < 0.001). The expression levels of the lncRNAs ZEB2-AS1 and TUG1 exhibited a significantly positive association in the AML group (P < 0.001). There was no difference in overall survival (OS) and disease-free survival (DFS) between the groups with low and high lncRNA TUG1 expression (P = 0.139 and 0.918, respectively). Furthermore, the AML cases with higher lncRNA ZEB2-AS1 expression levels had shorter DFS than patients with lower lncRNA ZEB2-AS1 expression levels (P = 0.014), while OS did not significantly differ between the studied cases with lower and higher lncRNA ZEB2-AS1 expression (P = 0.589).ConclusionOverexpression of lncRNA TUG1 could serve as a diagnostic biomarker for Egyptian adult AML cases, while lncRNA ZEB2-AS1 high expression could be regarded as an indicator of poor outcome in Egyptian adult AML studied cases.

P-401 Is cancer type associated with semen quality and infertility among men who desire fertility preservation?

Abstract Study question To investigate the association between cancer-types and semen-parameters before gonadotoxic-treatments, and to evaluate which patients have the highest risk of diminished spermatogenesis prior to therapy. Summary answer sperm quality among cancer patients before gonadotoxic treatment can differ according to the type of cancer. What is known already Many studies have reported impaired sperm quality at cancer diagnosis before any given gonadotoxic regiments. Except for testicular cancer and Hodgkin’s Lymphoma, baseline data on semen quality in case of different types of malignancies among male cancer patients are limited or based on low sample size Study design, size, duration A retrospective population-based cohort analysis was performed, 237 oncological male patients who were referred for fertility preservation between 1995-2020 within 90 days of cancer diagnosis and prior to cancer treatment Participants/materials, setting, methods The study population included 237oncological male patients who were referred to the Sperm Bank, Fertility, and IVF unit for the purpose of fertility preservation. Sperm analysis was performed within 90 days of cancer diagnosis and prior to therapy. The pre-treatment sperm analyses were based on the World Health Organization (WHO) guidelines Main results and the role of chance Histological examination of malignant diseases demonstrated 20 subtypes of cancers, the major groups included 49 patients with testicular cancer (TC), 72 patients with Hodgkin lymphoma (HD), 35 patients with other lymphoma, 29 patients with other hematological cancer, 16 with sarcoma and 36 with other solid malignant tumors. Our results show significant difference in sperm concentration between the different cancer groups (P value 0.007), the lowest median concentration of spermatozoa was found in the testicular cancer and sarcoma cancer patients 10 million per ml compared to the other cancer groups (other hematologic, Hodgkin lymphoma, other lymphoma and other solid tumors). Oligospermia was observed in 59% of testicular cancer patients and 50% of the sarcoma patients. Fertility outcomes were analyzed as a secondary objective. We found that only 37 patients' partners conceived and delivered offspring. Only 16.2% of those patients used their banked sperm and conceived via IVF-ICSI. We found that 20% of testicular cancer patients and other lymphoma patients including NHL conceived spontaneously after cancer diagnosis and treatment. Limitations, reasons for caution This is a retrospective cohort study and the oncology patients sample size is relatively small. Wider implications of the findings Our study emphasizes that sperm quality among cancer-patients before gonadotoxic-treatment can differ according to the cancer type. Significant reduction in sperm quality in testicular cancer patients was demonstrated, with a significant association was found between sperm concentration and various cancer-type. Further studies are warranted to confirm our results. Trial registration number not applicable

Anticancer Potential of Natural Chalcones: In Vitro and In Vivo Evidence.

There is no doubt that significant progress has been made in tumor therapy in the past decades. However, the discovery of new molecules with potential antitumor properties still remains one of the most significant challenges in the field of anticancer therapy. Nature, especially plants, is a rich source of phytochemicals with pleiotropic biological activities. Among a plethora of phytochemicals, chalcones, the bioprecursors of flavonoid and isoflavonoids synthesis in higher plants, have attracted attention due to the broad spectrum of biological activities with potential clinical applications. Regarding the antiproliferative and anticancer effects of chalcones, multiple mechanisms of action including cell cycle arrest, induction of different forms of cell death and modulation of various signaling pathways have been documented. This review summarizes current knowledge related to mechanisms of antiproliferative and anticancer effects of natural chalcones in different types of malignancies including breast cancers, cancers of the gastrointestinal tract, lung cancers, renal and bladder cancers, and melanoma.

Cryptococcosis in non-HIV/non-transplant hematological patients: A 12-year retrospective clinical analysis in a Peruvian referral cancer center.

e19536 Background: Globally, cryptococcal infection has become a public health challenge. However, relatively little is known about cryptococcal infection in non-HIV/non-transplant oncohematological patients. Methods: We developed a retrospective cohort study that includes hematological patients who had cryptococcosis infection seen in the Instituto Nacional de Enfermedades Neoplasicas between 2007 and 2018. We exclude HIV and transplant recipients patients. Results: During the 12-year study period, among 14908 individuals with hematological malignancies (HM), a total of 21 cases of cryptococcosis were identified, representing an incidence rate of 1.41 per 1000 HM diagnosed in our center. Non-Hodgkin lymphoma (NHL) (47.6%), acute leukemias (23.8%), multiple myeloma (19.1%), and Hodgkin lymphoma (9.5%). Three cases of adult T-cell leukemia/lymphoma were identified. The sub-group analysis showed that NHL (7.35 per 1000 NHL) and Multiple myeloma (4.59 per 1000 MM) had the highest incidence rates. Regarding the clinical presentation, the time between the diagnosis of cryptococcosis and HM was 42 (18–161) days. Cryptococcal fungemia and antigenemia was the most frequent diagnosis (85.7%), followed by pulmonary (52.4%) and central nervous system (38.1%) involvement. At the time of the diagnosis of cryptococcosis, 61.5% were receiving chemotherapy, 53.9% were in the induction phase, and 7.7% were on maintenance therapy. The use of immunosuppressants and chemotherapy within a month of the diagnosis of cryptococcosis was the most common risk factor (90.5%). Regarding the subanalysis performed between the different types of malignancies (NHL versus other HM), age at admission (p = 0.02), site of cryptococcosis presentation (p = 0.01), and lymphocyte count at admission (p = 0.01) were statistically different between these groups. In the NHL subgroup, there was less involvement of the lungs and higher fungemia (p = 0.01). The overall survival (OS) of our cohort at 15 and 120 days was 70% (95%CI: 0.43-0.86) and 51% (95%CI: 0.26-0.72), respectively. OS for patients with NHL was 57% at 15 days (95% CI: 0.17-0.83) and 42% at 120 days (95%CI:0.09-0.73). OS for other HM was 90% at 15 days (95%CI:0.47-0.98) and 60% at 120 days (95%CI: 0.25-0.82). Conclusions: Our cohort characterized the distinct clinical presentation, risk factors, and outcomes of cryptococcal infection in hematologic malignancies subgroups. NHL was the HM with the worst prognosis and the highest incidence rate. [Table: see text]

Ion Channels and Personalized Medicine in Gynecological Cancers.

Targeted therapy against cancer plays a key role in delivering safer and more efficient treatments. In the last decades, ion channels have been studied for their participation in oncogenic processes because their aberrant expression and/or function have been associated with different types of malignancies, including ovarian, cervical, and endometrial cancer. The altered expression or function of several ion channels have been associated with tumor aggressiveness, increased proliferation, migration, invasion, and metastasis of cancer cells and with poor prognosis in gynecological cancer patients. Most ion channels are integral membrane proteins easily accessible by drugs. Interestingly, a plethora of ion channel blockers have demonstrated anticancer activity. Consequently, some ion channels have been proposed as oncogenes, cancer, and prognostic biomarkers, as well as therapeutic targets in gynecological cancers. Here, we review the association of ion channels with the properties of cancer cells in these tumors, which makes them very promising candidates to be exploited in personalized medicine. The detailed analysis of the expression pattern and function of ion channels could help to improve the clinical outcomes in gynecological cancer patients.

SERS Immunosensors for Cancer Markers Detection.

Early diagnosis and monitoring are essential for the effective treatment and survival of patients with different types of malignancy. To this end, the accurate and sensitive determination of substances in human biological fluids related to cancer diagnosis and/or prognosis, i.e., cancer biomarkers, is of ultimate importance. Advancements in the field of immunodetection and nanomaterials have enabled the application of new transduction approaches for the sensitive detection of single or multiple cancer biomarkers in biological fluids. Immunosensors based on surface-enhanced Raman spectroscopy (SERS) are examples where the special properties of nanostructured materials and immunoreagents are combined to develop analytical tools that hold promise for point-of-care applications. In this frame, the subject of this review article is to present the advancements made so far regarding the immunochemical determination of cancer biomarkers by SERS. Thus, after a short introduction about the principles of both immunoassays and SERS, an extended presentation of up-to-date works regarding both single and multi-analyte determination of cancer biomarkers is presented. Finally, future perspectives on the field of SERS immunosensors for cancer markers detection are briefly discussed.

Characterization of the HLA-F ligandome in T-cell lymphoma

Abstract Identifying tumor-specific antigens across different types of malignancies and HLA haplotypes remains challenging. Recently, the expression of tumor-specific Human Endogenous Retroelements emerged as a potential new class of cytotoxic T-cell response mediators (1). HLA-F, a non-classic HLA-I molecule, has been hypothesized to present peptides to T-cells and to regulate immunity through interactions with distinct NK-cell receptors (2). HLA-F low genetic diversity and limited peptide repertoire represent an unexplored avenue in cancer immunotherapy. HLA-F-bound peptides were eluted from five patient-derived T-cell lymphoma cell lines and total T-cells purified from ten healthy donor PBMCs; Retroelement peptides were identified in the HLA-F ligandome. To quantify and validate their expression, RNA-sequencing data from the same samples were screened using ERVmap database (3). Lastly, to characterize their expression, we incorporate genome-wide characterization of DNA methylation patterns. We identified a set of retroelement peptides bound to HLA-F shared by patient-derived T-cell lymphoma cell lines but not total T-cells isolated from healthy donor PBMCs, suggesting a potential role of HLA-F in cancer-immune responses. Among those we characterized four tumor-specific retroelement peptides, validated by the presence of their RNA transcripts as well as by DNA integration and chromosomal location. Tumor-specific HLA-F-bound retroelement peptides hold great promise for the discovery of previously unknown tumor-specific markers and therapeutic targets. More importantly, the characterization of their immunogenicity may yield insights broadly applicable to a greater number of patients due to HLA-F monomorphism.

Can Chemotherapy Negatively Affect the Specific Antibody Response toward Core Vaccines in Canine Cancer Patients?

The life expectancy of our pets has been getting longer in recent years due to new therapeutic opportunities, better nutrition, and better diagnostic approaches. This positive effect, however, has been accompanied by a concomitant increase in neoplasms, particularly in canine patients. Therefore, veterinarians inevitably face new issues related to these diseases, poorly or never investigated in the past, such as the possible side effects resulting from chemotherapy. The aim of this study was to investigate whether and how chemotherapy influences the antibody response against CPV-2, CDV, and CAdV-1 in dogs vaccinated before starting chemotherapy. Twenty-one canine patients with different types of malignancies were sampled before, during, and after different chemotherapy protocols to determine their actual levels of seroprotection against CPV-2, CDV, and CadV-1 by using the in-practice test VacciCheck. Differences related to sex, breed size, type of tumor, and chemotherapy protocol were evaluated. No statistically significant changes in antibody protection emerged for any of the chemotherapy protocol used, suggesting that, contrary to expectation, chemotherapy does not have a marked immunosuppressive effect on the post-vaccine antibody response. These results, although preliminary, may be useful in improving the clinical approach to the canine cancer patient, helping veterinarians fully manage their patients, and enabling owners to feel more confident about their pets' quality of life.

Abstract 4989: Discovery and evaluation of ISM6466A, a novel covalent CDK12 inhibitor for the treatment of cancer

Abstract Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases. The CDK12/cyclin K complex regulates the elongation step of RNA transcription by phosphorylating Ser2 on the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II, and selectively affects the expression of genes, such as BRCA1 and BRCA2, involved in DNA Damage Response (DDR). CDK12 mutations as well as overexpression have been reported in different types of malignancies, making it an attractive cancer target. In this study, a series of covalent CDK12 inhibitors were designed and profiled in biochemical and cellular assays. ISM6466A was identified as a lead compound, demonstrating good in vitro efficacy, ADME properties, safety pharmacology profile (e.g., CYP, hERG), and a reasonable in vivo PK profile. Biochemically, ISM6466A exhibited reasonable selectivity over other CDKs, and inhibited cell proliferation in a panel of tumor cell lines with IC50 values in the nanomolar range (e.g., IC50 of ~100nM in the TNBC and AML cell lines, SUM149PT and MV4-11, respectively). Cell-based assays showed that ISM6466A has a selective inhibitory action for the phosphorylation of Ser2 on the CTD, but not for that of Ser5 or Ser7. Notably, ISM6466A demonstrated excellent in vivo anti-tumor efficacy in the SUM149PT breast cancer CDX model (Tumor Growth Inhibition, TGI, of 114% at 60 mg/kg QD) and in the MV4-11 AML CDX model (TGI of 95% at 30 mg/kg QD), without body weight loss. Data from an endpoint PKPD study in the MV4-11 CDX model revealed that ISM6466A inhibited phosphorylation of Ser2 on the CTD, and also inhibited DDR genes such as BRCA1 and ATR. Results from a 28-day rat DRF study revealed that the compound did not show evident signs of toxicity at the tested doses, suggesting a reasonable safety window for ISM6466A.In summary, the novel, covalent, small-molecule CDK12 inhibitor, ISM6466A, demonstrated excellent preclinical efficacy along with favorable drug-like properties. Our results underscore the therapeutic potential of ISM6466A for the treatment of cancer. Citation Format: Lihua Min, Hongfu Lu, Yihong Zhang, Jianping Wu, Xin Cai, Min Zheng, Hui Cui, Junwen Qiao, Xiao Ding, Sujata Rao, Feng Ren, Alex Zhavoronkov. Discovery and evaluation of ISM6466A, a novel covalent CDK12 inhibitor for the treatment of cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4989.

U-shaped association between serum IGF2BP3 and T2DM: A cross-sectional study in Chinese population.

To clarify the expression of N6-methyladenosine (m6 A) modulators involved in the pathogenesis of type 2 diabetes mellitus (T2DM). We further explored the association of serum insulin-like growth factor 2 mRNA-binding proteins 3 (IGF2BP3) levels and odds of T2DM in a high-risk population. The gene expression data set GSE25724 was obtained from the Gene Expression Omnibus, and a cluster heatmap was generated by using the R package ComplexHeatmap. Differential expression analysis for 13 m6 A RNA methylation regulators between nondiabetic controls and T2DM subjects was performed using an unpaired t test. A cross-sectional design, including 393 subjects (131 patients with newly diagnosed T2DM, 131 age- and sex-matched subjects with prediabetes, and 131 healthy controls), was carried out. The associations between serum IGF2BP3 concentrations and T2DM were modeled by restricted cubic spline and logistic regression models. Two upregulated (IGF2BP2 and IGF2BP3) and 5 downregulated (methyltransferase-like 3 [METTL3], alkylation repair homolog protein 1 [ALKBH1], YTH domain family 2 [YTHDF2], YTHDF3, and heterogeneous nuclear ribonucleoprotein [HNRNPC]) m6 A-related genes were found in islet samples of T2DM patients. A U-shaped association existed between serum IGF2BP3 levels and odds of T2DM according to cubic natural spline analysis models, after adjustment for body mass index, waist circumference, diastolic blood pressure, total cholesterol, and triglyeride. Multivariate logistic regression showed that progressively higher odds of T2DM were observed when serum IGF2BP3 levels were below 0.62 ng/mL (odds ratio 3.03 [95% confidence interval 1.23-7.47]) in model 4. Seven significantly altered m6 A RNA methylation genes were identified in T2DM. There was a U-shaped association between serum IGF2BP3 levels and odds of T2DM in the general Chinese adult population. This study provides important evidence for further examination of the role of m6 A RNA methylation, especially serum IGF2BP3 in T2DM risk assessment.