High-risk Subtypes Research Articles

Programmable Multiplexed Nucleic Acid Detection by Harnessing Specificity Defect of CRISPR-Cas12a.

CRISPR-Cas12a works like a sophisticated algorithm in nucleic acid detection, yet its challenge lies in sometimes failing to distinguish targets with mismatches due to its specificity limitations. Here, the mismatch profiles, including the quantity, location, and type of mismatches in the CRISPR-Cas12a reaction, are investigated and its various tolerances to mismatches are discovered. By harnessing the specificity defect of the CRISPR-Cas12a enzyme, a dual-mode detection strategy is designed, which includes approximate matching and precise querying of target sequences and develop a programmable multiplexed nucleic acid assay. With the assay, 14 high-risk human papillomavirus (HPV) subtypes are simultaneously detected, collectively responsible for 99% of cervical cancer cases, with attomolar sensitivity. Specifically, the assay not only distinguishes HPV16 and HPV18, the two most common subtypes but also detects 12 other high-risk pooled HPV subtypes. To enable low-cost point-of-care testing, the assay is incorporated into a paper-based microfluidic chip. Furthermore, the clinical performance of the paper-based microfluidic chip is validated by testing 75 clinical swab samples, achieving performance comparable to that of PCR. This programmable multiplexed nucleic acid assay has the potential to be widely applied for sensitive, specific, and simultaneous detection of different pathogens.

Subtype-specific transcription factors affect polyamine metabolism and the tumor microenvironment in breast cancer.

Polyamines play important roles in cell growth and proliferation. Polyamine metabolism genes are dysregulated in various tumors. Some polyamine metabolism genes are regulated by transcription factors. However, the transcription factors that regulate polyamine metabolism genes have not been completely identified. Additionally, whether any of the transcriptional regulations depend on tumor heterogeneity and the tumor microenvironment has not been investigated. We used bulk RNA-seq data to identify dysregulated polyamine metabolism genes and their transcription factors across breast cancer subtypes. Genes highly correlated with polyamine changes were obtained, and their subtype-specific expressions were checked in tumor microenvironment cells using single-cell RNA (scRNA)-seq data. Gene Ontology enrichmentanalysis was used to explore their molecular functions and biological processes, and survival analysis was used to examine the impact of these genes on therapeutic outcome. We first analyzed the dysregulation of polyamine synthesis, catabolism, and transport in four breast cancer subtypes. Genes such as AGMAT and CAV1 were dysregulated across all subtypes, while APRT, SAT1, and other genes were dysregulated in the more lethal subtypes. Among the dysregulated genes of polyamine metabolism, we focused on three genes (SRM, APRT, and SAT1) and identified their transcription factors (SPI1 and IRF1 correspond to SAT1, and IRF3 corresponds to SRM and APRT). With scRNA-seq data, we verified that these three transcription factors also regulated these three polyamine metabolism genes in the tumor microenvironment. Both bulk RNA-seq and scRNA-seq data indicated that these genes were specifically upregulated in high-risk breast cancer subtypes, such as the basal-like type. High expression of these genes corresponded to worse outcomes in the basal-like subtype under chemotherapy and radiation treatment. Our work identified three subtype-specific transcription factors that regulate three polyamine metabolism genes in high-risk breast cancer subtypes and the tumor microenvironment. Our results deepen the understanding of the role of polyamine metabolism in breast cancer and may help the clinical therapy of advanced breast cancer subtypes.

Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies

Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics. We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing analyses between high-risk groups. We examined two high-risk omics-defined groups in non-overlapping test sets (n=1133 NHW COPDGene, n=299 African American (AA) COPDGene, n=468 ECLIPSE). We defined "high activity" (low PRS, high TRS) and "severe risk" (high PRS, high TRS) subgroups. Participants in both subgroups had lower body-mass index (BMI), lower lung function, and alterations in metabolic, growth, and immune signalling processes compared to a low-risk (low PRS, low TRS) subgroup. "High activity" but not "severe risk" participants had greater prospective FEV1 decline (COPDGene:-51mL/year; ECLIPSE:-40mL/year) and proteomic profiles were enriched in gene sets perturbed by treatment with 5-lipoxygenase inhibitors and angiotensin-converting enzyme (ACE) inhibitors. Concomitant use of polygenic and transcriptional risk scores identified clinical and molecular heterogeneity amongst high-risk individuals. Proteomic and drug repurposing analysis identified subtype-specific enrichment for therapies and suggest prior drug repurposing failures may be explained by patient selection. National Institutes of Health.

First-Line Combination of R-CHOP with the PDE4 Inhibitor Roflumilast for High-Risk DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. The standard-of-care immunochemotherapy, R-CHOP, cures only about 60% of DLBCL patients. Improving this cure rate will likely require the effective translation of basic biology knowledge into clinical activities. We previously identified the cyclic-AMP/phosphodiesterase 4 (PDE4) axis as an important modulator of lymphomagenic processes. We also showed that the FDA-approved PDE4 inhibitor roflumilast can suppress B-cell receptor (BCR) signals, phosphoinositide 3-kinase (PI3K) activity and angiogenesis. These data suggested that combining roflumilast with R-CHOP may be beneficial in DLBCL. We conducted a single-center, single-arm, open-label, phase 1 study of roflumilast in combination with the standard of care, R-CHOP (Ro+R-CHOP), in pathologically proven, treatment-naïve, high-risk DLBCL patients. Ro+R-CHOP was safe, and at a median follow-up time of 44 months, 70% of patients were alive and disease free (median OS not reached, PFS 44% (95% CI, 21-92). In this pilot series, we found that the addition of roflumilast suppressed PI3K activity in peripheral blood mononuclear cells, and VEGF-A secretion in the urine. We also encountered preliminary evidence to suggest that the Ro+R-CHOP combination may be particularly beneficial to patients diagnosed with high-risk genetic subtypes of DLBCL, namely MCD and A53. These initial findings suggest that roflumilast may be an alternative agent able to inhibit BCR/PI3K activity and angiogenesis in DLBCL, and that the testing of Ro+R-CHOP in a larger series of genetically characterized tumors is warranted. This study was registered at ClinicalTrials.gov, number NCT03458546.

Diagnostic profiles among suicide decedents with and without borderline personality disorder.

Borderline personality disorder (BPD) is a debilitating condition characterized by pervasive instability across multiple major domains of functioning. The majority of persons with BPD engage in self-injury and up to 10% die by suicide - rendering persons with this condition at exceptionally elevated risk of comorbidity and premature mortality. Better characterization of clinical risk factors among persons with BPD who die by suicide is urgently needed. We examined patterns of medical and psychiatric diagnoses (1580 to 1700 Phecodes) among persons with BPD who died by suicide (n = 379) via a large suicide death data resource and biobank. In phenotype-based phenome-wide association tests, we compared these individuals to three other groups: (1) persons who died by suicide without a history of BPD (n = 9468), (2) persons still living with a history of BPD diagnosis (n = 280), and (3) persons who died by suicide with a different personality disorder (other PD n = 589). Multivariable logistic regression models revealed that persons with BPD who died by suicide were more likely to present with co-occurring psychiatric diagnoses, and have a documented history of self-harm in the medical system prior to death, relative to suicides without BPD. Posttraumatic stress disorder was more elevated among those with BPD who died by suicide relative to the other PD group. We found significant differences among persons with BPD who died by suicide and all other comparison groups. Such differences may be clinically informative for identifying high-risk subtypes and providing targeted intervention approaches.

Frequent Occurrence of High-Risk Basal Cell Carcinoma in Xeroderma Pigmentosum: A Histopathological Insight From an Indian Cohort.

Xeroderma pigmentosum (XP) is a genodermatosis, characterized both by premature aging and significantly increased risk of non-melanoma and melanoma skin cancers at an early age. However, limited literature is available on the common histopathological subtypes of basal cell carcinoma (BCC) in these patients. In this ambispective case series, we recruited patients of XP who had either a currently present skin tumor or previously excised one, provided their histopathological sections were available. Cytogenetic analysis was performed in all the patients. The histopathological findings were recorded by two trained dermatopathologists. Of 22 recruited patients with XP, 12 patients had 41 BCCs, and 23 (56.09%) of them showed a high-risk histopathological subtype. Basosquamous carcinoma (10, 24.39%) was the most frequent high-risk tumor followed by infiltrative variant (7, 17.07%). Mixed-histopathological subtypes were noted in six (14.63%) cases, and all of them had a high-risk component. The low-risk subtypes included nodular (n = 17, 41.46%) and superficial BCC (1, 2.43%). Though a deep dermal involvement was seen in 27 (65.85%) lesions, none showed a perineural invasion or necrosis. Three (7.31%) lesions showed ulceration, while 10 (24.39%) showed presence of pigmentation. A frequent occurrence of high-risk basal cell carcinoma was noted in patients with XP-mandating creation of appropriate treatment and follow-up strategies in these patients.

NIMG-60. SUBTYPING GLIOBLASTOMA FROM JOINT CLUSTERING OF IMAGING AND GENOMIC DATA

Abstract PURPOSE To comprehensively unravel the heterogeneity of glioblastoma, we developed a subtyping method using integrated imaging and genomic data. METHODS We assembled a retrospective cohort of 571 IDH-wildtype glioblastoma patients, obtaining pre-operative multi-parametric MRI (T1, T1-GD, T2, T2-FLAIR, DSC, DTI) scans (available for 462 patients) and targeted next-generation sequencing (NGS) data (available for 355 patients). We extracted 971 radiomic features from these MRI scans, selecting 12 significant dimensions through L21-norm minimization guided by 13 key driver genes from the five most frequently altered pathways in glioblastoma compared to healthy controls (RB1, P53, MAPK, PI3K, and RTK). Subtypes were identified using a joint clustering approach that integrated radiomics and genomics. RESULTS Our method identified three glioblastoma subtypes with distinct risk levels: high-risk (subtype 1), medium-risk (subtype 2), and low-risk (subtype 3), each characterized by their differential overall survival outcomes (Kaplan-Meier analysis, p < 0.05). The intensities of axial diffusivity in enhancing tumor regions and radial diffusivity in non-enhancing cores increased across three subtypes. All subtypes shared a common tendency for more frequent mutation co-occurrence pattern in [TP53,RB1] but exhibited unique molecular characteristics. For example, subtype 1 displayed a relatively high frequency of co-occurring mutations in [TP53,KDR] and [NOTCH2,MDM4]; subtype 2 had six co-occurring pairs [TP53,KDR], [PTPN11,NF1], [RB1,FUBP1], [PTEN,CIC], [PTEN,KRAS], and [NOTCH2,CDKN2A]; subtype 3 showed six co-occurring pairs [PTPN11,NF1], [PDGFRA,NF1], [NTRK1,NOTCH2], [MET,ATRX], [KRAS,KDR], and [FGFR2,DNMT3A] plus four significant patterns of mutual exclusivity in [TP53,PTPN11], [TP53,EGFR], [EGFR,RB1], and [EGFR,NF1]. CONCLUSION Our study discovered distinct glioblastoma subtypes, revealing complex patterns and structures across multiple data modalities without relying on prior clinical assumptions. This is promising to help enhance the precision of diagnosis and treatment of glioblastoma.

HPV infection status among women of all ages in Jinshan District, Shanghai.

We explored the prevalence of human papillomavirus (HPV) infection among women in Jinshan District, Shanghai. We analyzed all HPV testing samples sent from our unit between December 2023 and April 2024. We reported the HPV prevalence overall, by age, and by subtype. In total, 3788 women aged 16 to 90 years had HPV test results. The prevalence of infection with any HPV subtype was 17.9%. The HPV prevalence by age group was: ≤30 years, 15.4%; 31-40 years, 14.7%; 41-50 years, 17.0%; 51-60 years, 22.4%; >60 years, 31.0%. Among HPV-positive women, 80.6% had infection with one subtype, 16.4% had dual infection, and 3.1% had three or more subtypes detected. We found 640 cases (16.9%) of infection with high-risk HPV subtypes and 139 cases (5.04%) of infection with low-risk HPV subtypes. The most common high-risk subtypes were HPV 52, 53, 58, and 16; the most common low-risk subtypes were HPV 81, 70, and 42. We detected ≥1 HPV subtype among most women in our study. The prevalence of HPV was lowest in younger women and highest in women age >60 years. Tailored strategies for older women are needed to prevent HPV infection and cervical cancer.

Human papillomavirus as a potential etiological factor and biomarker in bladder carcinogenesis: A molecular epidemiological study

Bladder cancer is a major public health concern, and the identification of novel biomarkers is crucial for improving its diagnosis and treatment. Human Papillomavirus (HPV) has been linked to various neoplasms, though its relevance to bladder cancer (BC) is hardly known. In this study, we aimed at evaluating the presence of HPV in bladder cancer tissues and determine its utility as a potential biomarker. Nested PCR, using consensus primers MY09/11, GP5+/6+ and reference plasmids targeting HPVs 16, 18, 33, 11, 6 and 31 were employed on 50 samples from patients with bladder carcinoma. Among the 50 bladder cancer patients analyzed, 23 (46 %) tested positive for HPV, while 27 (54 %) tested negative and significant association was identified between HPV infection and key clinical parameters including tumor stage (P = 0.031**), tumor grade (P = 0.007**) and muscle invasion (P = 0.046*). High-risk HPV genotypes, specifically type 16 was the most prevalent and was detected in 11 (47.8 %) of bladder cancer cases. Single HPV infection 18 (78.2 %) was more common than co-infection cases 5 (21.7 %), though no statistical significance was observed between infection type and patients' clinicopathological parameters. Our findings revealed a significant association between HPV infection and advanced tumor characteristics, particularly with higher tumor grade and pathological T-stage. High-risk HPV genotypes, notably types 16 and 18, were the most frequently observed, suggesting a potential role for high-risk HPV subtypes in bladder tumor progression. These findings underscore the possible contribution of HPV in bladder carcinogenesis and suggest that infection with the virus, particularly with high-risk strains, could serve as a valuable biomarker for early bladder cancer diagnosis and risk assessment. Targeting HPV in bladder cancer tissues may thus pave the way for HPV-based diagnostic and prognostic tools and tailored therapeutic approaches.

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL) is a high-risk subtype of acute lymphoblastic leukemia characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab, an anti-CD20 monoclonal antibody is administered to adult BCP-ALL patients with ≥20% CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of rituximab in combination with TKI. Consequently, we examined the influence of TKI on the antitumor effectiveness of anti-CD20 monoclonal antibodies by evaluating levels of CD20 on the cell surface and conducting in vitro functional assays. All tested TKI were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of rituximab-mediated complement- dependent cytotoxicity. Interestingly, these TKI displayed varied effects on natural killer (NK) cell-mediated antibody- dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-monoclonal antibody-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity in patients' blood, as determined by an ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKI for combination therapy with anti-CD20 monoclonal antibodies.

KMT2A-rearranged acute lymphoblastic leukaemia

KMT2A-rearranged acute lymphoblastic leukaemia (ALL) represents a high risk subtype of childhood ALL. Historical treatment strategies have comprised of intensification with conventional chemotherapy. However, outcomes have remained consistently poor compared to the advances that have been seen for other ALL subtypes, particularly for infants diagnosed before their first birthday. The advent of novel immunotherapeutic approaches has led to a change in the treatment paradigm, with the integration of blinatumomab to the current suite of clinical trials for KMT2A-rearranged ALL expected to result in marked improvements. Furthermore, significant progress has been made to understand the unique biology of KMT2A-rearranged ALL, which has led to the development of novel agents that directly target the KMT2A complex or dysregulated proteins/pathways. Clinical trials are currently poised to evaluate therapies such as venetoclax and menin inhibitors, offering further hope for achieving a cure. In this review, we discuss the remarkable progress that has been made for KMT2A-rearranged ALL, leading to much optimism for improved outcomes in the future.

Breast relapse of myeloid sarcoma and SARS-CoV-2 infection following hematopoietic stem cell transplantation in mixed-phenotype acute leukemia: a case report

Abstract Background Mixed-phenotype acute leukemia is a rare, high-risk subtype of acute leukemia. Myeloid sarcoma is a localized tumor formed by the proliferation and infiltration of primitive or immature myeloid cells outside the bone marrow. It is often an extramedullary manifestation of acute myeloid leukemia, and imaging lacks specificity, leading to potential misdiagnosis. Case Presentation A female patient diagnosed with mixed-phenotype acute leukemia achieved complete remission after chemotherapy and allogeneic hematopoietic stem cell transplantation. However, a relapse occurred in the breast after transplantation. The patient achieved local control through mastectomy and removal of the axillary lymph nodes on the affected side. Unfortunately, during the subsequent course of chemotherapy, the patient died of a severe pulmonary infection caused by coronavirus disease 2019. Conclusion Continuous treatment and monitoring of mixed-phenotype acute leukemia patients are essential, especially for those with extramedullary manifestations (such as breast involvement).

Aggressiveness evaluation of borderline serous ovarian tumors by analysis of Psammoma bodies present in cancer tissues using micro-FTIR spectroscopy

Borderline ovarian tumor is a type of tumor with generally low malignant potential. However, these tumors pose diagnostic challenges with benign and malignant epithelial ovarian tumors because the clinical symptoms are similar and investigation procedures for specific diagnosis are still debated. In addition, a small number of borderlines transform into high-grade serous ovarian carcinoma with a poor prognosis. Therefore, tools improving a better characterization of high-risk subtypes of borderline tumors to enable understanding of possible unfavorable evolution are essential for patients’ management. Psammoma bodies (PBs) are microcalcifications found both in serous epithelial ovarian cancer and serous borderline tumors with possible correlation with disease progression.In this work, the chemical composition of PBs found in the tissues of borderline, high-grade and low-grade ovarian tumors was evaluated using micro-FTIR spectroscopy. Applying principal component analysis to spectral data, it was observed that among the borderline tumors analyzed (1-bl,2-bland3-bl), the PBs of3-blshowed a different chemical content from that of the PBs of the high-grade and low-grade tumors, while the PBs of1-bland2-blappeared to have similar chemical content to the PBs of high- and low-grade tumors. The discriminating wavenumbers were found to be those related to carbonate CO32− (1454, 1413 cm−1and 872 cm−1) and phosphate PO43−(1018 cm−1and 960 cm−1) present in microcalcifications. A higher ratio between peak intensities at 1413 cm−1and 1018 cm−1(I1413/I1018) was observed in the PBs of3-blcompared with those of high- and low-grade ovarian carcinoma patients, which correlates with higher CO32− content. On the other hand, the PBs of1-bland2-blshowed a CO32−level close to that of the PBs of high- and low-grade patients. Several studies on microcalcifications in breast carcinoma have reported that increased carbonate content is related to decreased tumor aggressiveness. Therefore, case bl-3 appeared to be the less aggressive. The results obtained from FTIR analysis were in agreement with histopathological tumor classification and molecular analysis for BRAFV600E. The FTIR technique could become a reliable tool for identifying borderline low- and high-risk tumors.

Prostaglandin E2 suppresses KCNH1 gene expression and inhibits the proliferation of CaSki cervical cells through its four prostanoid PTGER subtypes

The main risk factor for cervical cancer is the persistent infection of high-risk HPV subtypes, notably HPV16. Another contributing factor is proinflammatory prostaglandin E2 (PGE2), a lipid abundantly found in seminal fluid. PGE2, along with its receptors (PTGER1-4), contributes to cancer development; however, its specific role in the proliferation of cervical cancer models with high HPV16 copy numbers remains unclear. In this study, we investigated the effects of PGE2 on the proliferation of CaSki cells, a cell line with a high HPV16 viral load. Surprisingly, PGE2 inhibited CaSki cell proliferation, while it increased the proliferation of SiHa, HeLa, and C-33 A cervical cancer cells. The effect of PGE2 on CaSki cell proliferation was specific, as estradiol increased cell growth. Furthermore, PGE2 suppressed expression and promoter activity of the cervical tumoral marker KCNH1. To discern the specific role of each receptor in cell proliferation, we generated stable CaSki cell lines overexpressing each receptor alongside control cells with an empty vector. Notably, PGE2 significantly inhibited cell proliferation in all stable transfected CaSki cells, suppressing oncogenic KCNH1 expression and its promoter activity. In conclusion, our findings indicate that PGE2 inhibits the proliferation of CaSki cervical cancer cells with a high HPV16 load, at least in part, by suppressing the expression of the oncogenic KCNH1 gene.

Transcriptionally Active Human Papillomavirus in Male Genital Lichen Sclerosus, Penile Intraepithelial Neoplasia, and Penile Squamous Cell Carcinoma

Penile intraepithelial neoplasia (PeIN) and penile squamous cell carcinoma (PeSCC) are both thought to be associated with male genital lichen sclerosus (MGLSc) and HPV infection via dichotomous pathways: (i) undifferentiated (u)PeIN and warty/basaloid PeSCC are thought to be HPV-related, whereas (ii) differentiated (d)PeIN and ‘usual’ PeSCC are considered HPV-independent. Tissue arrays were constructed from MGLSc, u- and dPeIN, usual type PeSCC, and unaffected tissues. Staining for p16, and for high risk (HR) and low risk (LR) HPV subtypes via RNAscope were performed. The expression of HPV RNA and p16 were quantified, and condign statistical comparisons were undertaken. HR HPV was prevalent in uPeIN (77%) and less so in PeSCC (46%) and was exiguous or absent in all other tissues. LR HPV was only observed in two tissue cores. Strong p16 staining exhibited 96.15% sensitivity and 100% specificity for HR HPV. Transcriptionally active HPV is unlikely to be implicated in MGLSc and dPeIN, although clearly important in uPeIN. The high prevalence of HR HPV in ‘usual’ PeSCC challenges the existing paradigm. Strong p16 positivity was a reliable surrogate marker for the detection of transcriptionally active HR HPV.

Prevalence of 14 high-risk human papillomavirus subtypes among volunteers of cervical cancer screening by Papanicolaou smear cytology from a tertiary care institute of Assam, India

Abstract: BACKGROUND: In India, cervical cancer is the second most prevalent cancer among women, constituting 18.3% of all cases. Persistent high-risk human papillomavirus (HPV) infection is a well-established risk factor for cervical cancer. OBJECTIVES: This study aimed to assess the prevalence of 14 high-risk HPV subtypes and their association with abnormal cytology among women in Upper Assam. MATERIALS AND METHODS: This descriptive cross-sectional study was conducted from February 2022 to April 2023 at a tertiary care center in Assam. A total of 100 women aged 23-72 years underwent cervical sample collection for HPV DNA analysis via real-time polymerase chain reaction and cytological examination of Papanicolaou (PAP) smears. RESULTS: The overall HPV prevalence was 13%, with 10% testing positive for HPV 16/18 and 6% for other high-risk subtypes. Coinfection with HPV 16/18 and other subtypes was found in 3% of cases. The mean age of HPV-positive participants was 46 years. Cytology results showed 87% normal, 11% inflammatory changes, and 2% epithelial cell abnormalities. The Chi-square analysis (α = 0.05) showed no significant association between age (P = 0.24), religion (P = 0.49), or education (P = 0.57) and HPV positivity, but the study showed a significant association of HPV infection with menstrual cycle (P = 0.04). The study also showed a significant association between cervical cytology and HPV positivity (P = 0.0087). DISCUSSION: The present study’s findings on the prevalence of all 14 high-risk HPV subtypes contribute new insights to the existing literature, although the slightly lower prevalence may be attributed to the sample size and demographic factors. The findings emphasize the need for regular screening by PAP smear as well as by HPV DNA detection, as cytological abnormalities were detected even in those without HPV infection. CONCLUSION: Along with 16/18 HPV subtypes, a longitudinal study may offer important insights into the development of coinfections and the other 12 subtypes of HPV infection, as well as the spectrum of dysplasia and in situ cervical cancer.

Philadelphia-like B-cell acute lymphoblastic Leukaemia: Disease features and outcomes in the era of immunotherapy.

Philadelphia chromosome (Ph)-like acute lymphoblastic leukaemia (ALL) is a high-risk subtype with a gene expression profile similar to Ph-positive ALL, due to activation of tyrosine kinase signalling. To understand the clinical implications of Ph-like ALL, this single-centre retrospective study evaluates outcomes in 268 adults, largely Hispanic ALL patients treated between 2013 and 2024, with a subgroup analysis of 139 haematopoietic stem cell transplantation (HSCT) patients. ALL subtypes included 68 (25.4%) Ph-like, 89 (33.2%) Ph-positive, and 111 (41.4%) Ph-negative. Ph-like patients were the youngest age at diagnosis (p = 0.007), most likely to have refractory disease (p < 0.001), and least likely to achieve minimal residual disease (MRD) negativity after induction (p = 0.031). Relative to Ph-negative ALL, Ph-like achieved worse event-free survival (EFS) (HR = 1.66; 95% CI 1.12-2.46; p = 0.012), whereas Ph-positive had improved EFS (HR = 0.60; 95% CI 0.38-0.93; p = 0.024) and cumulative incidence of relapse (CIR) (HR = 0.59; 95% CI 0.35-0.99; p = 0.046). Within the transplant subgroup, Ph status did not impact disease-free survival (DFS), CIR, or overall survival (OS). However, patients who received blinatumomab within 1-year pre-HSCT had improved DFS (HR = 0.43; 95% CI 0.20-0.94; p = 0.034) and CIR (HR = 0.26; 95% CI 0.09-0.75; p = 0.13). In conclusion, our data suggest that Ph-like is less likely to respond to standard induction therapy and HSCT may result in similar survival outcomes to Ph-negative ALL.

Identification and validation of a novel five-gene signature in high-risk MYCN-not-amplified neuroblastoma

ObjectiveHigh-risk neuroblastoma patients often have poor outcomes despite multi-treatment options. The risk stratification of high-risk MYCN-not-amplified (HR-MYCN-NA) patients remains difficult. This study aims to identify a gene set signature that can help further stratify HR-MYCN-NA patients for a potential personalized therapeutic strategy.MethodsThree microarrays and one single-cell RNA sequence dataset were acquired and analyzed. Firstly, the prognostic-related genes (PRGs) in HR-MYCN-NA tumor cells were identified using TARGET-NB and GSE137804 datasets. Then, the prognostic model was established by LASSO-Cox regression, and verified in external cohort (GSE49710, GSE45547). Moreover, a time-dependent receiver operating characteristic curve (ROC) and area under the ROC (AUC) was used to assess survival prediction. A nomogram was established to predict the 1-, 3- and 5-year overall survival (OS) of HR-MYCN-NA patients.ResultsIn the training set, a five-PRGs signature, which include GAL, GFRA3, MARCKS, PSMD13, and ZNHIT3 genes, was identified and successfully stratified HR-MYCN-NA patients into ultra-high risk (UHR) and high-risk (HR) subtypes (HR = 4.29, P < 0.001). ROC curve analysis confirmed its predictive power (AUC = 0.74–0.82), suggesting a good predictive efficacy. Consistently, high-risk scores also predicted worse OS (HR = 2, P = 0.033) in the external validation dataset (AUC = 0.67–0.71). Moreover, the overall C-index of the nomogram was 0.75 (P < 0.001), which indicated good agreement between the observed and predicted survival rates. Further integrating the five PRGs signature with clinical factors, these 5 gene signature (HR = 4.45, P < 0.001) and tumor grade (HR = 4.15, P = 0.02) were found to be independent prognostic factors for HR-MYCN-NA patients.ConclusionThe novel five PRGs signature could well predict the survival of HR-MYCN-NA patients, which may provide constructive information for these subsets.

Randomized dose-response trial of n-3 fatty acids in hormone receptor negative breast cancer survivors- impact on breast adipose oxylipin and DNA methylation patterns.

Increasing evidence suggests the unique susceptibility of estrogen receptor and progesterone receptor negative (ERPR-) breast cancer to dietary fat amount and type. Dietary n-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may modulate breast adipose fatty acid profiles and downstream bioactive metabolites to counteract pro-inflammatory, pro-carcinogenic signaling in the mammary microenvironment. To determine effects of ~1 to 5 g/d EPA+DHA over 12 months on breast adipose fatty acid and oxylipin profiles in women with ERPR(-) breast cancer, a high-risk molecular subtype. We conducted a 12-month randomized controlled, double-blind clinical trial of ~5g/d vs ~1g/d DHA+EPA supplementation in women within 5 years of completing standard therapy for ERPR(-) breast cancer Stages 0-III. Blood and breast adipose tissue specimens were collected every 3 months for biomarker analyses including fatty acids by gas chromatography, oxylipins by LC-MS/MS, and DNA methylation by reduced-representation bisulfite sequencing (RRBS). A total of 51 participants completed the 12-month intervention. Study treatments were generally well-tolerated. While both doses increased n-3 PUFAs from baseline in breast adipose, erythrocytes, and plasma, the 5g/d supplement was more potent (n =51, p <0.001). The 5g/d dose also reduced plasma triglycerides from baseline (p =0.008). Breast adipose oxylipins at 0, 6, and 12 months showed dose-dependent increases in unesterified and esterified DHA and EPA metabolites (n =28). Distinct DNA methylation patterns in adipose tissue after 12 months were identified, with effects unique to the 5g/d dose group (n =17). Over the course of 1 year, EPA+DHA dose-dependently increased concentrations of these fatty acids and their derivative oxylipin metabolites, producing differential DNA methylation profiles of gene promoters involved in metabolism-related pathways critical to ERPR(-) breast cancer development and progression. These data provide evidence of both metabolic and epigenetic effects of n-3 PUFAs in breast adipose tissue, elucidating novel mechanisms of action for high-dose EPA+DHA-mediated prevention of ERPR(-) breast cancer.

Identification of two molecularly and prognostically distinct subtypes in acral melanoma using network prediction method.

Acral melanoma, characterized by its aggressiveness and poor prognosis compared to other melanoma subtypes, poses significant challenges in clinical management. However, the molecular underpinnings driving the biological and clinical features of this disease remain poorly understood. In this study, our aim was to elucidate the molecular landscape and the correlation between subtypes and clinical features of acral melanoma. We conducted comprehensive analyses to dissect the molecular characteristics of acral melanoma, employing a combination of multi-omics data analysis and network-based disease gene prediction algorithms. Single-cell RNA-Seq data were utilized to investigate the contribution of immunocytes to the molecular classification of acral melanoma. Additionally, we used clinical samples to validate the correlation between new subtypes and the prognosis of acral melanoma and the expression of subtype markers and verified the interaction between macrophages and acral melanoma cells at cellular level. Our study reveals the existence of two distinct subtypes of acral melanoma exhibiting marked differences in clinical behaviour, cellular and molecular mechanisms. We identified a robust biomarker panel (EREG, VSIG4, FCGR3A and RAB20) that accurately distinguishes these two subtypes with an impressive AUC of 0.946, validated using clinical samples. Subtype I, characterized by thinner Breslow thickness, demonstrates a favourable prognosis, whereas Subtype II represents a high-risk subtype with a propensity for dermal invasion. Notably, the signature gene EREG of Subtype I is enriched in FCN1+ macrophages, known for promoting inflammatory and immune responses. Conversely, signature genes VSIG4 and FCGR3A of Subtype II are enriched in SPP1+ macrophages, which exhibit significant crosstalk with tumour cells. Our findings significantly enhance the understanding of the molecular landscape of acral melanoma and offer novel insights into its clinical management by identifying distinct subtypes and potential therapeutic targets. The findings have to be confirmed in different cohorts in the future for full validation.