Emerging biomarkers and molecular targets for precision medicine in cervical cancer.

Cervical cancer remains a significant global health burden, necessitating innovative approaches for improved diagnostics and personalized treatment strategies. Precision medicine has emerged as a promising paradigm, leveraging biomarkers and molecular targets to tailor therapy to individual patients. This review explores the landscape of emerging biomarkers and molecular targets in cervical cancer, highlighting their potential implications for precision medicine. By integrating these biomarkers into comprehensive diagnostic algorithms, clinicians can identify high-risk patients at an earlier stage, enabling timely intervention and improved patient outcomes. Furthermore, the identification of specific molecular targets has paved the way for the development of targeted therapies aimed at disrupting key pathways implicated in cervical carcinogenesis. In conclusion, the evolving landscape of biomarkers and molecular targets presents exciting opportunities for advancing precision medicine in cervical cancer. By harnessing these insights, clinicians can optimize treatment selection, enhance patient outcomes, and ultimately transform the management of this devastating disease.

8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia.

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

Interpreter usage and associations with latent tuberculosis infection treatment acceptance and completion in the USA among non-U.S.-born persons, 2012-2017.

BACKGROUND: Latent tuberculosis infection (LTBI) screening and treatment interventions that are tailored to optimize acceptance among the non-U.S.-born population are essential for U.S. tuberculosis elimination. We investigated the impact of medical interpreter use on LTBI treatment acceptance and completion among non-U.S.-born persons in a multisite study. METHODS: The Tuberculosis Epidemiologic Studies Consortium was a prospective cohort study that enrolled participants at high risk for LTBI at ten U.S. sites with 18 affiliated clinics from 2012 to 2017. Non-U.S.-born participants with at least one positive tuberculosis infection test result were included in analyses. Characteristics associated with LTBI treatment offer, acceptance, and completion were evaluated using multivariable logistic regression with random intercepts to account for clustering by enrollment site. Our primary outcomes were whether use of an interpreter was associated with LTBI treatment acceptance and completion. We also evaluated whether interpreter usage was associated treatment offer and whether interpreter type was associated with treatment offer, acceptance, or completion. RESULTS: Among 8,761 non-U.S.-born participants, those who used an interpreter during the initial interview had a significantly greater odds of accepting LTBI treatment than those who did not use an interpreter. There was no association between use of an interpreter and a clinician's decision to offer treatment or treatment completion once accepted. Characteristics associated with lower odds of treatment being offered included experiencing homelessness and identifying as Pacific Islander persons. Lower treatment acceptance was observed in Black and Latino persons and lower treatment completion by participants experiencing homelessness. Successful treatment completion was associated with use of shorter rifamycin-based regimens. Interpreter type was not associated with LTBI treatment offer, acceptance, or completion. CONCLUSIONS: We found greater LTBI treatment acceptance was associated with interpreter use among non-U.S.-born individuals.

Total Synthesis and Cytotoxicity Evaluation of Pareitropone and Analogues.

A concise synthesis of pareitropone by oxidative cyclization of a phenolic nitronate is delineated. The use of TMSOTf as an additive to promote the facile formation of a strained norcaradiene intermediate provides convenient access to highly condensed multicyclic tropones in high yields. This synthesis is modular, efficient, and scalable, highlighting the synthetic utility of radical anion coupling reactions in annulation reactions. This work is discussed in the context of total syntheses of the tropoloisoquinoline alkaloids. Also included are the preparation of several congeners and a brief description of their biological activities.

Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery.

Epigenetic dysregulation has been reported in multiple cancers including leukemias. Nonetheless, the roles of the epigenetic reader Tudor domains in leukemia progression and therapy remain unexplored. Here, we conducted a Tudor domain-focused CRISPR screen and identified SGF29, a component of SAGA/ATAC acetyltransferase complexes, as a crucial factor for H3K9 acetylation, ribosomal gene expression, and leukemogenesis. To facilitate drug development, we integrated the CRISPR tiling scan with compound docking and molecular dynamics simulation, presenting a generally applicable strategy called CRISPR-Scan Assisted Drug Discovery (CRISPR-SADD). Using this approach, we identified a lead inhibitor that selectively targets SGF29's Tudor domain and demonstrates efficacy against leukemia. Furthermore, we propose that the structural genetics approach used in our study can be widely applied to diverse fields for de novo drug discovery.

Milk production and nitrogen excretion of grazed dairy cows in response to plantain (Plantago lanceolata) content and lactation season.

Objective: The study aimed to quantify milk production and urinary nitrogen (UN) excretion of dairy cows grazing pastures containing varying contents of plantain (Plantago lanceolata) in different seasons, under a typical farm practice. Methods: Four pasture treatments: perennial ryegrass (Lolium perenne) - white clover (Trifolium repens) (RGWC), RGWC + low plantain rate, RGWC + medium plantain rate, and RGWC + high plantain rate, were established in four adaptation areas (1 ha each) and 20 experimental plots (800 m2 each), and rotationally grazed by dairy cows over 14 grazing events during two lactation years. In each grazing (8-9 days), 60 or 80 Jersey-Friesian lactation cows were assigned to their pasture treatments, adapted to their pastures over the first six days, then each group of 15 or 20 cows were randomly allocated for grazing in five treatment plots over a two or three-day measurement period. Milk, urine, and faecal samples were collected from individual cows during the measurement period. Results: The pasture treatments did not affect milk production, the yield and composition of milk solids, protein, fat, and lactose. However, cows grazing pastures containing between 17-28% dietary plantain reduced UN concentration by 15-27%, decreased UN excretion by 4-9%, and increased urine volume by 22-40%, compared to grazing the RGWC pasture. The change in UN concentration, and urine volume were associated with plantain proportion in the diet and were greater during late summer and autumn than during early summer. Conclusion: Incorporating 17%-28% dietary plantain with RGWC pastures can reduce the risk of nitrogen losses from pastoral systems, while maintaining the milk production of dairy cows.

Tuberculosis Infectiousness is Associated with Distinct Clinical and Inflammatory Profiles.

Interrupting transmission events to prevent new acquisition of infection and disease is a critical part of tuberculosis (TB) control efforts. However, knowledge gaps in understanding the biology and determinants of TB transmission, including poor estimates of individual infectiousness and the lack of accurate and convenient biomarkers, undermine efforts to develop interventions. Cough-generated aerosol cultures have been found to predict TB transmission better than any microbiological or clinical markers in cohorts from Uganda and Brazil. We hypothesized that highly infectious individuals with pulmonary TB (defined as positive for cough aerosol cultures) have elevated inflammatory markers and unique transcriptional profiles compared to less infectious individuals (negative for cough aerosol cultures). We performed a prospective, longitudinal study using a cough aerosol sampling system as in other studies. We enrolled 142 participants with treatment-naïve pulmonary TB in Nairobi, Kenya, and assessed the association of clinical, microbiologic, and immunologic characteristics with Mtb aerosolization and transmission in 143 household members. Contacts of the forty-three aerosol culture-positive participants (30%) were more likely to have a positive IGRA (85% vs 53%, P = 0.005) and a higher median IGRA IFNγ level (P < 0.001, median 4.25 IU/ml (0.90-5.91) vs. 0.71 (0.01-3.56)) compared to aerosol culture-negative individuals. We found that higher bacillary burden, younger age, and larger mean upper arm circumference were associated with positive aerosol cultures. In addition, novel host inflammatory profiles, including elevated serum C-reactive protein and sputum cytokines, were associated with aerosol culture status. Notably, we found pre-treatment whole blood transcriptional profiles associated with aerosol culture status, independent of bacillary load. Together, these findings suggest that TB infectiousness is associated with epidemiologic characteristics and inflammatory signatures and that these features may be used to identify highly infectious persons. These results provide new public health tools and insights into TB pathogenesis.

TBscreen: A passive cough classifier for tuberculosis screening with a controlled dataset.

Recent respiratory disease screening studies suggest promising performance of cough classifiers, but potential biases in model training and dataset quality preclude robust conclusions. To examine tuberculosis (TB) cough diagnostic features, we enrolled subjects with pulmonary TB (N = 149) and controls with other respiratory illnesses (N = 46) in Nairobi. We collected a dataset with 33,000 passive coughs and 1600 forced coughs in a controlled setting with similar demographics. We trained a ResNet18-based cough classifier using images of passive cough scalogram as input and obtained a fivefold cross-validation sensitivity of 0.70 (±0.11 SD). The smartphone-based model had better performance in subjects with higher bacterial load {receiver operating characteristic-area under the curve (ROC-AUC): 0.87 [95% confidence interval (CI): 0.87 to 0.88], P < 0.001} or lung cavities [ROC-AUC: 0.89 (95% CI: 0.88 to 0.89), P < 0.001]. Overall, our data suggest that passive cough features distinguish TB from non-TB subjects and are associated with bacterial burden and disease severity.

Pharmacological profiling of a berbamine derivative for lymphoma treatment.

ABSTRACT: Ca2+/calmodulin-dependent protein kinase II γ (CAMKIIγ) has been identified as a potential target for treating cancer. Based on our previous study of berbamine (BBM) as a CAMKIIγ inhibitor, we have synthesized a new BBM derivative termed PA4. Compared with BBM, PA4 showed improved potency and specificity and was more cytotoxic against lymphoma and leukemia than against other types of cancer. In addition to indirectly targeting c-Myc protein stability, we demonstrated that its cytotoxic effects were also mediated via increased reactive oxygen species production in lymphoma cells. PA4 significantly impeded tumor growth in vivo in a xenograft T-cell lymphoma mouse model. Pharmacokinetics studies demonstrated quick absorption into plasma after oral administration, with a maximum concentration of 1680 ± 479 ng/mL at 5.33 ± 2.31 hours. The calculated oral absolute bioavailability was 34.1%. Toxicity assessment of PA4 showed that the therapeutic window used in our experiments was safe for future development. Given its efficacy, safety, and favorable pharmacokinetic profile, PA4 is a potential lead candidate for treating lymphoma.

Sensitive Blood-Based Detection of HIV-1 and Mycobacterium tuberculosis Peptides for Disease Diagnosis by Immuno-Affinity Liquid Chromatography-Tandem Mass Spectrometry: A Method Development and Proof-of-Concept Study.

BACKGROUND: Novel approaches that allow early diagnosis and treatment monitoring of both human immunodeficiency virus-1 (HIV-1) and tuberculosis disease (TB) are essential to improve patient outcomes. METHODS: We developed and validated an immuno-affinity liquid chromatography-tandem mass spectrometry (ILM) assay that simultaneously quantifies single peptides derived from HIV-1 p24 and Mycobacterium tuberculosis (Mtb) 10-kDa culture filtrate protein (CFP10) in trypsin-digested serum derived from cryopreserved serum archives of cohorts of adults and children with/without HIV and TB. RESULTS: ILM p24 and CFP10 results demonstrated good intra-laboratory precision and accuracy, with recovery values of 96.7% to 104.6% and 88.2% to 111.0%, total within-laboratory precision (CV) values of 5.68% to 13.25% and 10.36% to 14.92%, and good linearity (r2 > 0.99) from 1.0 to 256.0 pmol/L and 0.016 to 16.000 pmol/L, respectively. In cohorts of adults (n = 34) and children (n = 17) with HIV and/or TB, ILM detected p24 and CFP10 demonstrated 85.7% to 88.9% and 88.9% to 100.0% diagnostic sensitivity for HIV-1 and TB, with 100% specificity for both, and detected HIV-1 infection earlier than 3 commercial p24 antigen/antibody immunoassays. Finally, p24 and CFP10 values measured in longitudinal serum samples from children with HIV-1 and TB distinguished individuals who responded to TB treatment from those who failed to respond or were untreated, and who developed TB immune reconstitution inflammatory syndrome. CONCLUSIONS: Simultaneous ILM evaluation of p24 and CFP10 results may allow for early TB and HIV detection and provide valuable information on treatment response to facilitate integration of TB and HIV diagnosis and management.

Artificial intelligence and allied subsets in early detection and preclusion of gynecological cancers.

Gynecological cancers including breast, cervical, ovarian, uterine, and vaginal, pose the greatest threat to world health, with early identification being crucial to patient outcomes and survival rates. The application of machine learning (ML) and artificial intelligence (AI) approaches to the study of gynecological cancer has shown potential to revolutionize cancer detection and diagnosis. The current review outlines the significant advancements, obstacles, and prospects brought about by AI and ML technologies in the timely identification and accurate diagnosis of different types of gynecological cancers. The AI-powered technologies can use genomic data to discover genetic alterations and biomarkers linked to a particular form of gynecologic cancer, assisting in the creation of targeted treatments. Furthermore, it has been shown that the potential benefits of AI and ML technologies in gynecologic tumors can greatly increase the accuracy and efficacy of cancer diagnosis, reduce diagnostic delays, and possibly eliminate the need for needless invasive operations. In conclusion, the review focused on the integrative part of AI and ML based tools and techniques in the early detection and exclusion of various cancer types; together with a collaborative coordination between research clinicians, data scientists, and regulatory authorities, which is suggested to realize the full potential of AI and ML in gynecologic cancer care.

Regression of ovarian cancer xenografts by depleting or inhibiting RLIP.

Ovarian cancer (OC) is the most prevalent and deadly cancer of the female reproductive system. Women will continue to be impacted by OC-related morbidity and mortality. Despite the fact that chemotherapy with cisplatin is the main component as the first-line anticancer treatment for OC, chemoresistance and unfavorable side effects are important obstacles to effective treatment. Targets for effective cancer therapy are required for cancer cells but not for non-malignant cells because they are expressed differently in cancer cells compared to normal cells. Targets for cancer therapy should preferably be components that already exist in biochemical and signalling frameworks and that significantly contribute to the development of cancer or regulate the response to therapy. RLIP is an important mercapturic acid pathway transporter that is crucial for survival and therapy resistance in cancers, therefore, we examined the role of RLIP in regulating essential signalling proteins involved in relaying the inputs from upstream survival pathways and mechanisms contributing to chemo-radiotherapy resistance in OC. The findings of our research offer insight into a novel anticancer effect of RLIP depletion/inhibition on OC and might open up new therapeutic avenues for OC therapy.

Anti-adipogenic properties of clock activator chlorhexidine and a new derivative.

Background: The circadian clock exerts temporal control of metabolic pathways to maintain homeostasis, and its disruption leads to the development of obesity and insulin resistance. In adipose tissue, key regulators of clock machinery orchestrate adipogenic processes via the Wnt signaling pathway to impact mature adipocyte development. Methods: Based on the recent finding of chlorhexidine as a new clock activator, we determined its potential anti-adipogenic activities in distinct adipogenic progenitor models. Furthermore, we report the structural optimization of chlorhexidine leading to the discovery of analogs with improved efficacy in inhibiting adipogenesis. Results: In adipogenic progenitors with Per2::dLuc luciferase reporter, Chlorhexidine shortened clock period length with induction of core clock components. Consistent with its clock-activating function, Chlorhexidine robustly suppressed the lineage commitment and maturation of adipogenic mesenchymal precursors, with comparable effect on inhibiting preadipocyte terminal differentiation. Mechanistically, we show that Chlorhexidine induces signaling components of the Wnt pathway resulting in activation of Wnt activity. Via modification of its chemical scaffold, we generated analogs of chlorhexidine that led to the identification of CM002 as a new clock- activating molecule with improved anti-adipogenic activity. Conclusions: Collectively, our findings uncovered the anti-adipogenic functions of a new class of small molecule clock activators. These compounds provide novel chemical probes to dissect clock function in maintaining metabolic homeostasis and may have therapeutic implications in obesity and associated metabolic disorders.

Extubation to High-Flow Nasal Cannula in Infants Following Cardiac Surgery: A Retrospective Cohort Study.

High-flow nasal cannula (HFNC) therapy is commonly used in the pediatric intensive care unit (PICU) for postextubation respiratory support. This hypothesis-generating retrospective cohort study aimed to compare postextubation PICU length of stay in infants extubated to HFNC and low flow oxygen (LF) in PICU following cardiac surgery. Of 136 infants (newborn to 1 year) who were intubated and mechanically ventilated in PICU following cardiac surgery, 72 (53%) were extubated to HFNC and 64 (47%) to LF. Compared with patients extubated to LF, those extubated to HFNC had significantly longer durations of cardiopulmonary bypass (152 vs. 109 minutes; p = 0.002), aortic cross-clamp (90 vs. 63 minutes; p = 0.003), and invasive mechanical ventilation (3.2 vs. 1.6 days; p < 0.001), although demographic and preoperative clinical variables were similar. No significant difference was observed in postextubation PICU length of stay between HFNC and LF groups in unadjusted analysis (3.3 vs. 2.6 days, respectively; p = 0.19) and after controlling for potential confounding variables (F [1,125] = 0.17, p = 0.68, R 2 = 0.16). Escalation of therapy was similar between HFNC and LF groups (8.3 vs. 14.1%; p = 0.41). HFNC was effective as rescue therapy for six patients in the LF group requiring escalation of therapy. Need for reintubation was similar between HFNC and LF groups (8.3 vs. 4.7%; p = 0.5). Although extubation to HFNC was associated with a trend toward longer postextubation PICU length of stay and was successfully used as rescue therapy for several infants extubated to LF, our results must be interpreted with caution given the limitations of our study.

Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of ß2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal.

TET2 is recurrently mutated in acute myeloid leukemia (AML) and its deficiency promotes leukemogenesis (driven by aggressive oncogenic mutations) and enhances leukemia stem cell (LSC) self-renewal. However, the underlying cellular/molecular mechanisms have yet to be fully understood. Here, we show that Tet2 deficiency significantly facilitates leukemogenesis in various AML models (mediated by aggressive or less aggressive mutations) through promoting homing of LSCs into bone marrow (BM) niche to increase their self-renewal/proliferation. TET2 deficiency in AML blast cells increases expression of Tetraspanin 13 (TSPAN13) and thereby activates the CXCR4/CXCL12 signaling, leading to increased homing/migration of LSCs into BM niche. Mechanistically, TET2 deficiency results in the accumulation of methyl-5-cytosine (m5C) modification in TSPAN13 mRNA; YBX1 specifically recognizes the m5C modification and increases the stability and expression of TSPAN13 transcripts. Collectively, our studies reveal the functional importance of TET2 in leukemogenesis, leukemic blast cell migration/homing, and LSC self-renewal as an mRNA m5C demethylase.

Small molecule targeting of transcription-replication conflict for selective chemotherapy.

Targeting transcription replication conflicts, a major source of endogenous DNA double-stranded breaks and genomic instability could have important anticancer therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes. Through a rational drug design approach, we identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells. AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin regions, while inducing DNA double-stranded breaks in a transcription-dependent manner. Attenuation of RPB1 interaction with PCNA, by a point mutation in RPB1's PCNA-binding region, confers resistance to AOH1996. Orally administrable and metabolically stable, AOH1996 suppresses tumor growth as a monotherapy or as a combination treatment but causes no discernable side effects. Inhibitors of transcription replication conflict resolution may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability.