OBJECTIVE:To investigate to describe outcomes of conization or expectant management for women with persistent (>24 months) low-grade cervical intra-epithelial neoplasia. METHODS:This is a retrospective analysis focusing on five-year outcomes after persistent, histologically confirmed, low-grade cervical intra-epithelial neoplasia undergoing conization or expectant management. RESULTS:Charts of 219 women with persistent low-grade cervical lesions were retrieved. Overall, 98 (44.7%) and 121 (55.3%) women had conization and observation, respectively. Patients receiving conization were older than patients having observation (43 (range, 24-77) vs. 39 (range, 25-68) years; p=0.013). Focusing on the group of patients receiving conization, 16 (16.3%) women were diagnosed with CIN2+. The five-year risk of secondary conization was 5% (n=5). Focusing on patients having observation (n=121), 18 (14.8%) patients received conization, after a median of 16.5 (range, 6-30) months. Seven (5.8%) and 11 (9.1%) patients were diagnosed with persistent CIN1 and CIN2+, respectively. Not fully visible squamous-columnar junction at colposcopic examination (p=0.035) was associated with CIN2+ occurrence. No invasive cancer was observedConclusions:Conization for persistent low-grade cervical intra-epithelial neoplasia revealed "occult" CIN2+ in 16% of patients. However, expectant management appears safe and effective in this context, in women with fully visible squamous columnar junction. The decision between conization and expectant management should be discussed on an individual basis.

INTRODUCTION:We estimated cancer mortality figures for 2026 in five major Asian countries and Australia, with a specific focus on prostate cancer. METHODS:We computed country- and sex-specific annual age-standardized mortality rates (ASRs) for all cancers combined and for the 10 most common cancer sites, using data from the WHO and the United Nations Population Division up to 2022 or the most recent available year. We predicted figures for 2026 and estimated the number of avoided cancer deaths in 1994-2026. RESULTS:Predicted mortality rates for all cancers combined in 2026 are favourable across all considered countries and in both sexes, with the largest declines expected in the Republic of Korea (-20.5% in males and -10.2% in females compared with 2020-2022). In 2026, the lowest predicted male rate is expected in the Philippines (72.1 per 100 000), and the highest one in Australia (92.3 per 100 000). Among females, the lowest predicted ASR (42.2 per 100 000) is in the Republic of Korea, whereas the highest one (74.1 per 100 000) in the Philippines. Trends are generally favourable for lung, stomach, colorectum, and other major neoplasms considered, except pancreas. Predicted prostate cancer mortality is favourable in all countries and across all age groups. Rates are expected to remain low in Hong Kong SAR, Japan, and the Republic of Korea, with ASRs below 4 per 100 000 males. Since the 1993 observed peak rate, an estimated 132 000 total cancer deaths were avoided in Hong Kong SAR, 75 000 in Israel, 1 366 000 in Japan, 720 000 in the Republic of Korea, 328 000 in Australia, and 102 000 among men in the Philippines. CONCLUSIONS:Declining cancer mortality is predicted in the countries considered. These trends largely reflect smoking cessation along with improvements in prevention, early detection, and treatment. However, substantial geographic disparities persist, highlighting the need for strengthened cancer control strategies, particularly in ageing populations.

Sleep duration has been proposed to influence the risk of colorectal cancer (CRC). An involvement of inflammation, metabolic disorders, and gut permeability has been suggested. We investigated the relationship between sleep duration and CRC risk and examined whether sleep duration was associated with selected inflammatory and metabolic markers, and markers of gut permeability and bacterial translocation from the intestine to bloodstream. We used data from an Italian case-control study including 212 subjects (71 CRC cases and 141 tumor-free subjects). Sleep habits were collected through a questionnaire, including information on the average hours of sleep per night. We measured serum C-reactive protein (CRP) and glycemia by the ILab System, lipopolysaccharide-binding protein and zonulin by ELISA kit, and blood bacterial 16S rRNA gene copies by quantitative PCR and sequencing. We derived the odds ratios (OR) and corresponding 95% confidence intervals (CI) of CRC according to sleep duration from multiple logistic regression models. There was a positive association between long sleep duration and CRC risk, OR, 3.36 (95% CI, 1.08-10.53) for ≥ 9 compared to 7-8 h. For ≤ 6 h, the OR was 1.62 (95% CI, 0.84-3.29). BMI, circulating levels of CRP and glycemia, and a species of Streptococcus appeared to be higher in subjects reporting ≥9 vs. 7-8 h of sleep. Our data show a positive relationship between long sleep on CRC risk and suggest possible insights on inflammation, metabolic disorders, and possibly gut barrier dysfunction explaining this association.

BACKGROUND:Soft tissue sarcomas (STSs) are rare malignancies with largely unknown etiology; the role of anthropometry and physical activity has been rarely explored. METHODS:We analyzed 2011-2019 data of an Italian, multicenter, hospital-based case-control study including 498 incident, histologically confirmed STS cases and 969 controls. Self-reported height, weight, and physical activity data were collected; hip and waist circumferences were measured in 76% of cases and 61% of controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multiple-adjusted logistic regression models. RESULTS:Compared with BMI < 25 kg/m 2 , the ORs for BMI one year prior to diagnosis/interview were 1.05 (95% CI: 0.80-1.37) for 25-29.9 kg/m 2 and 1.28 (95% CI: 0.90-1.83) for ≥30 kg/m 2 . The OR was increased for BMI 25-29.9 kg/m 2 at age 30; no association emerged for BMI at age 50 years. For waist circumference, the ORs were 1.93 (95% CI: 1.38-2.70) for >102 cm in males or >88 cm in females, and 3.54 (95% CI: 2.40-5.22) for the highest versus the lowest tertile. For waist-to-hip ratio, the ORs were 1.18 (95% CI: 0.81-1.71) for the intermediate, and 2.81 (95% CI: 1.95-4.03) for the highest tertile. Subjects reporting ≥5 h/week of total or intermediate/high intensity leisure-time physical activity at age 30-39 years had ORs of 0.63 (95% CI: 0.40-1.00) and 0.56 (95% CI: 0.32-1.00), respectively. CONCLUSION:These findings show a positive association between abdominal adiposity and STS risk, and an inverse association with regular leisure-time physical activity.

Bilateral prophylactic mastectomy (BPM) or contralateral risk-reducing mastectomy (CRRM) are considered in CDH1 carriers as a strategy to reduce lobular breast cancer (LBC) risk in women. In this study we aimed to evaluate the overall number of these procedures reported in literature. We conducted a literature search and a scoping review through the PUBMED database. We identified eleven studies eligible for our interest. Overall numbers, frequencies, geographic distribution, family history, and post-operative histopathological findings of BPM or CRRM were the main outcomes considered. Articles reporting information about BPM or CRRM were reported only in Europe and North America. A total of 75 (32.1%) women were treated with any mastectomy (BPM or CRRM), from a population of 234 positive at CDH1 genetic testing; 81.3% of these women, were treated in North America and 18.7% in Europe. In total, 69.3% of surgical procedures were BPM and 30.7% were CRRM; 76.9% of BPMs were performed in North America, and 23.1% in Europe. Instead, 91.3% of CRRMs were reported in North America, and 8.7% in Europe, respectively. A positive family history for BC was documented in 81.8% and post-operative histopathological findings described at least one in situ LBC in nearly all breast specimens. In conclusion, BPM or CRRM were performed in about 1/3 of women with germline CDH1 pathogenic or likely pathogenic variants; studies were reported only in Western countries. Family history for BC in CDH1 carriers and detection of LCIS in post-operative specimens were also frequently described.

Germline PALB2 variants confer a moderate/high-risk for breast cancer (BC). Recent reports described an increasing attention in suggesting bilateral prophylactic mastectomy (BPM), for healthy carriers, or contraleral risk-reducing mastectomy (CRRM) and/or therapeutic mastectomy for women with BC. In this study, we aimed to calculate systematically the overall number of these procedures reported in literature. We revised all articles using systematic research through the PUBMED database. Overall numbers, frequencies, geographic distribution, family history, and post-operative histopathological analysis of BPM or CRRM were the main outcomes considered. Among 51 studies, 10 articles fulfilled our aim. All BPM or CRRM were performed in North America. One-hundred and forty-two (6.6

Conventional age-based breast cancer screening ignores substantial inter-individual risk variation, contributing to overdiagnosis, false positives, and missed opportunities for earlier detection in high-risk women. Mammography-based artificial intelligence (AI) may enable risk-stratified screening and more efficient workflows. To systematically review evidence on mammography-based AI for personalized breast cancer screening, covering risk prediction, detection/triage, decision support, and associated ethical, economic, and equity implications. We searched MEDLINE/PubMed, Embase, Scopus, Web of Science, and the Cochrane Library (January 2015–November 2025) for studies evaluating AI-enabled personalization in breast cancer screening. Two reviewers independently screened 612 records, assessed 77 full texts, and included 30 studies; data were synthesized narratively. Image-based deep-learning risk models consistently outperformed traditional clinical risk tools and enriched future cancers within small high-risk strata, including cancers presenting as interval cancers in recent validations. Prospective trials and real-world implementations indicate that AI-supported reading can maintain or modestly improve cancer detection while reducing radiologist workload by roughly 40–50

Abstract Women in leading positions in medical research remain underrepresented and face systemic barriers to career advancement, including implicit biases and stereotypes. To explore these issues, and envisage feasible solutions, we conducted a cross-sectional qualitative study using a 33-item questionnaire. The survey was completed by 82 Italian senior academic female researches with an h-index higher than 60 in biomedical research. Major fields of study were biology, neurosciences, immunology, metabolism, genomics, pharmacology and oncology/cancer biology. This cohort offers insights into the experiences, struggles, and achievements of highly successful women in medical research. Findings reveal persistent gender biases and societal expectations slowing or hindering women’s career progression, with only 17% of respondents expressing satisfaction with gender parity in opportunities within the field Almost all (91%) reported challenges with work-life balance and lack of institutional support, many respondents emphasized the underrepresentation of women in leadership, with 74% highlighting the need to increase female participation in decision-making roles. Additionally, 61% advocated for promoting more women to senior positions toward achieving gender equality in the field. 89%, experienced at least one gender-related obstacle during their career while 42% were tempted to resign from their professional role. These results highlight the persistent structural and cultural obstacles that even top-performing women face in the field. Targeted strategies such as mentorship, education to counteract bias, flexible work policies, and equitable promotion policies are required for empowerment and to foster a more inclusive environment for current and future generations of women scientists. The study also highlights the resilience, dedication, and motivation of women academic medical researchers. Their sense of responsibility, passion for science, and the search of both personal and social support systems are crucial factors contributing to their persistence in the field, encouraging younger women to pursue a career in medical research. Citation Format: Adriana Albini, Elisabetta Vercesi, Eva Negri, Giovanni Corso, Sonia Levi, Douglas McClain Noonan. Barriers and challenges to women leadership in medical research and how to overcome them [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3693.

Background Invasive lobular breast carcinoma (ILC) differs from invasive ductal breast carcinoma (IDC) with respect to genetic alterations and risk factors. We aimed to quantify differences in the prevalence of germline BRCA1/2 mutations between these two patients’ populations. Materials and methods We conducted a systematic literature search to extract data on the association between BRCA1/2 mutation status and breast cancer (BC) histological subtype (ILC and IDC). Summary odds ratios (SOR) and 95% CI were calculated using random effects univariate and bivariate models and between-study heterogeneity investigated through meta-regression and subgroup analyses. Results Twelve studies, published between 1998 and 2025, were considered, including 8004 BC women. BRCA1 mutations were significantly less frequent in patients with ILC than IDC (SOR=0.32, 95%CI (0.16-0.65)) whereas no association was found overall for BRCA2 (SOR=1.28, 95%CI (0.95-1.72)). The difference between the association with BRCA1 and BRCA2 was statistically significant (p-value<0.001). There was no indication of publication bias in BRCA1 (Egger’s and Begg’s test p-value=0.23, 0.12). The between study heterogeneity was 29% in BRCA1 and 0% in BRCA2. Excluding papers with high risk of bias, BRCA2 mutations were more frequent in patients with ILC than in IDC (SOR=2.56, 95%CI (1.15-5.7)). This association was primarily driven by the bivariate random-effects model, which accounts for the correlation between BRCA1 and BRCA2 estimates. Conclusions In studies with lower risk of bias, germline BRCA2 mutations were more frequent in patients with ILC than IDC. Conversely, BRCA1 mutations are more frequently observed in IDC, particularly among younger patients and those with a positive family history of BC.

Importance:Invasive lobular carcinoma (ILC) represents the second most common histologic subtype of breast cancer (BC), yet its genomic landscape and clinical implications remain less well defined compared with invasive ductal carcinoma. Understanding genetic predisposition in ILC may improve risk assessment and guide tailored clinical management. Objectives:To investigate the prevalence and clinical outcomes of germline pathogenic or likely pathogenic variants (PVs) in BC predisposition genes among women with ILC and to assess the prognostic utility of polygenic risk scores (PRSs) in this population. Design, Setting, and Participants:This prospective, longitudinal cohort study was conducted at the European Institute of Oncology, Milan, Italy, from May 16, 2022, to January 31, 2025. Women diagnosed with primary ILC were enrolled and underwent multigene panel testing of 113 genes using next-generation sequencing. Follow-up data were collected until January 31, 2023. Statistical analysis was performed in January 2026. Main Outcomes and Measures:The primary outcome was BC-free survival, defined as the time from surgery to ipsilateral recurrence, contralateral disease, distant metastasis, or BC-related death. Secondary outcomes included overall survival and PRS distribution across genetic subgroups. Results:A total of 414 White women (mean [SD] age, 53.7 [9.7] years; 211 [51.0%] with postmenopausal status) with ILC were tested. No significant associations were found between germline variant subgroups and patients' characteristics. PVs were identified in 46 patients (11.1%), with 20 (4.8%) carrying variants in moderate- to high-risk BC genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, FANCM, PALB2, RAD51C, RAD51D, STK11, TP53, and PTEN). The group of women carrying PVs in moderate- to high-risk BC genes had significantly reduced 5-year BC-free survival compared with the rest of cohort (62.2% [95% CI, 32.3%-82.0%] vs 92.1% [95% CI, 87.6%-95.0%]; hazard ratio, 3.91; 95% CI, 1.99-7.67; P < .001). PRS analysis did not reveal statistically significant differences in relapse risk across quartiles of PRS, and no association was found between PRSs and germline variant status. Conclusions and Relevance:This cohort study of women with primary ILC identified a clinically relevant subset of patients carrying moderate- to high-risk germline PVs who exhibited an increased risk of early relapse. Although PRSs did not show prognostic value in this setting, multigene panel testing findings may refine genetic counseling and inform surveillance and therapeutic strategies in lobular breast tumors.

Background Cancer screening is a cornerstone of cancer control in Europe yet marked disparities persist in access, implementation, and quality assurance among national or regional programs. Building on the EU Council’s 2022 recommendations and the European Union’s Beating Cancer Plan, the European Consensus Project (ECP) was established to provide harmonized, evidence-based recommendations for major cancer screening programs and to promote a shift toward risk-adapted, technology-enabled, and equitable prevention models. Methods A structured expert panel meeting was convened under the auspices of the European Cancer Prevention Organization, integrating systematic literature review and multidisciplinary discussion to formulate validated, evidence-based recommendations. For each primary cancer site (breast, lung, colo-rectum, cervix, prostate, and stomach), systematic literature reviews identified evidence on reductions in mortality, stage distribution, participation, cost-effectiveness, and organizational quality. Results The consensus reaffirmed the evidence of mortality reduction with organized breast, lung, colorectal, and cervical screening, endorsed structured risk-adapted prostate-specific antigen testing for prostate cancer, and recommended Helicobacter pylori ‘screen-and-treat’ strategies for gastric cancer in high-incidence regions. Insights into future perspectives of liquid biopsy approaches are outlined. Conclusion The ECP Consensus outlines a European roadmap for precision screening, grounded in quality assurance, individual risk stratification, artificial intelligence integration, and public health literacy. These recommendations align with the EU Mission on Cancer and Europe’s Beating Cancer Plan, providing a harmonized roadmap toward precision prevention and equitable implementation of screening across Europe.

INTRODUCTION:Ductal carcinoma in situ (DCIS) is a non-invasive breast cancer increasingly detected through screening. While microcalcifications are the most common feature, a subset lacks them, posing diagnostic and management challenges. We investigated the relationship between radiological presentation (calcified vs. non-calcified) and the risk of upstaging to invasive carcinoma. MATERIALS AND METHODS:We retrospectively analyzed 196 patients with biopsy-proven DCIS who underwent surgery between 2000 and 2023. Ninety-eight (98) non-calcified cases diagnosed via ultrasound-guided vacuum-assisted biopsy were matched with 98 calcified cases diagnosed via stereotactic vacuum-assisted biopsy, based on age, grade, and macroscopic removal. We investigated the associations between upstaging and potential predictors, including calcification status, age at biopsy, lesion size, and histologic grade at biopsy. RESULTS:The overall underestimation rate was 13.8% (27/196). Non-calcified DCIS showed a higher upstaging rate than calcified DCIS (19% vs. 8%; multivariable OR for calcified DCIS: 0.31, 95% CI: 0.12-0.78, p = 0.013). Larger lesions increased the risk of underestimation (OR per 5 mm: 1.21, 95% CI: 1.06-1.38, p = 0.005), while age was not significant (OR per 5 years: 1.01, p = 0.91). CONCLUSIONS:Non-calcified DCIS and larger lesion size seemed independently associated with upstaging to invasive carcinoma, highlighting the clinical relevance of radiological presentation for risk stratification.

This study aimed to evaluate the role of adjuvant HPV vaccination in women undergoing conization for cervical intraepithelial neoplasia. This prospective study assessed factors influencing recurrence in patients undergoing conization for high-grade cervical dysplasia. After conization, patients were counseled on the potential benefits of vaccination. We compared outcomes between two groups: women who underwent conization with adjuvant human papillomavirus (HPV) vaccination and observation versus conization with observation only. Data from 281 patients were analyzed, comprising 168 (59.8%) patients in the conization-only group and 113 (40.2%) patients in the conization-plus vaccination group. Vaccinated patients were younger than nonvaccinated patients (38 vs. 45 years, P < 0.001). Positive surgical margins were more frequently observed in the vaccinated group compared with the nonvaccinated group (9.7 vs. 3.6%; P = 0.038). Median follow-up was shorter in the vaccinated group, although this difference was not statistically significant (24.9 vs. 27.8 months; P = 0.395). The risk of developing HPV-related lesions was similar between the vaccinated and nonvaccinated groups ( P = 0.594, log-rank test). Likewise, the need for reconization did not differ significantly between the groups ( P = 0.593, log-rank test). Multivariate analysis showed no significant impact of HPV vaccination on postoperative outcomes [hazard ratio (HR): 0.50, 95% confidence interval (CI): 0.15–1.68) for any lesion; HR: 0.90, 95% CI: 0.47–1.73 for reconization]. This study indicates that adjuvant HPV vaccination does not significantly affect short-term outcomes in women undergoing conization for cervical dysplasia. Ongoing randomized trials will provide more robust evidence to clarify the role of adjuvant vaccination in this setting.

TNF receptor-associated factor 2 (TRAF2) plays a crucial role in both physiological and pathological processes. It takes part in the regulation of cell survival and death, tissue regeneration, development, endoplasmic reticulum stress response, autophagy, homeostasis of the epithelial barrier and regulation of adaptive and innate immunity. Initially identified for its interaction with TNF receptor 2 (TNFR2), TRAF2 contains a TRAF domain that enables homo- and hetero-oligomerization, allowing it to interact with multiple receptors and signaling molecules. While best known for mediating TNFR1 and TNFR2 signaling, TRAF2 also modulates other receptor pathways, including MAPK, NF-κB, and Wnt/β-catenin cascades. By regulating NF-κB-inducing kinase (NIK), TRAF2 is a key activator of the alternative NF-κB pathway, linking it to inflammatory diseases, immune dysfunction, and tumorigenesis. In the innate immune system, TRAF2 influences macrophage differentiation, activation, and survival and stimulates natural killer cell cytotoxicity. In the adaptive immune system, it represses effector B- and T-cell activity while sustaining regulatory T-cell function, thus promoting immune suppression. The lack of fine-tuning of TRAF2 activity leads to excessive NF-kB activation, driving chronic inflammation and autoimmunity. Although TRAF2 can act as a tumor suppressor, it is predominantly described as a tumor promoter, as its expression has been correlated with increased metastatic potential and poorer prognosis in several types of cancer. Targeting TRAF2 or TRAF2-dependent signaling pathways might represent a promising anti-cancer therapeutic strategy.

Endometriosis is one of the most common gynecological benign disease. Epidemiological evidence suggests a potential association between endometriosis and cancer risk. Accumulating evidence highlighted the risk of ovarian cancer, particularly endometrioid and clear cell subtypes. Few studies reported a modest correlation between endometriosis and various solid tumors including, endometrial cancer, and melanoma. However, inconsistencies remain across studies. Additionally, some data indicate an increased risk of melanoma, basal cell carcinoma, and non-Hodgkin lymphoma, underscoring the multifaceted nature of cancer risk in women with endometriosis. The underlying mechanisms include chronic inflammation, oxidative stress, hormonal dysregulation, and genetic alterations, such as mutations in ARID1A , PTEN , and KRAS , which contribute to the shared pathology between endometriosis and cancer. This paper explores the complex association between endometriosis and cancer, focusing on specific malignancies. This review emphasizes the importance of understanding the shared mechanisms between endometriosis and cancer. Although most women with endometriosis will not develop cancer, further research is essential to unravel the molecular pathways linking these conditions and enhance long-term outcomes for affected women.

Leading societies have established guidelines that vary significantly regarding recommendations for the surgical management of pulmonary carcinoids (PC). We aimed to assess current guidelines and recommendations for PC surgical management, benchmark their methodological quality, and identify factors that may influence their effectiveness in guiding surgical practice. Literature was sought to identify relevant guidelines for the management of PC. Each guideline was evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool and rated on a seven-point scale for items and domains. Five observers assessed four guidelines (developed by ENETS in 2015, ESMO in 2021, NANETS in 2021, and NCCN in 2020). In Scope and Purpose and Stakeholder Involvement, the NCCN guideline achieved the highest score. In Rigor of Development, NANETS and ENETS achieved the highest score. In Clarity of Presentation, ENETS guidelines scored the highest score. For applicability, NCCN received the highest score. All guidelines got the highest score in the Rigor of Development and Clarity of Presentation domains, whereas the Applicability domain received the lowest score. The methodological quality of guidelines on the surgical management of PC varies significantly. The findings underscore the need for future guidelines to prioritize practical implementation in clinical and surgical practice, ensuring that recommendations reflect best practices and effectively meet surgeons’ needs. Based on our AGREE II appraisal, the ENETS and ESMO guidelines might be recommended as a model for developing future recommendations and guidelines.

Hereditary diffuse gastric and lobular breast cancer (HDGLBC) is an inherited cancer syndrome predominantly characterized by diffuse gastric cancer (DGC) and lobular breast cancer (LBC). LBC often serves as the initial manifestation of HDGLBC, even in the absence of DGC symptoms. Despite advancements in medical technology and treatment, gastric cancer remains a major health burden globally. Approximately 1%–3% of gastric cancers are attributed to hereditary cancer syndromes, with pathogenic variants in the CDH1 gene being a significant contributor. CDH1 encodes E-cadherin, a protein essential for cell–cell adhesion in epithelial tissues. CDH1 inactivation through germline mutations leads to a high risk of developing DGC and LBC. The inactivation process involves a ‘second hit’ mechanism, commonly promoter methylation, leading to the loss of E-cadherin expression and subsequent tumorigenesis. Additionally, mechanisms such as loss of heterozygosity and somatic mutations contribute to CDH1 inactivation. Current research highlights the complexity of these mechanisms and their role in HDGLBC pathogenesis. Therapeutic strategies targeting these pathways, including epigenetic drugs and synthetic lethal approaches, show promise in restoring CDH1 function and inhibiting tumor progression. Given the aggressive nature of HDGLBC, early diagnosis and personalized treatment plans are crucial. Surveillance for LBC in CDH1 mutation carriers should be prioritized, considering prophylactic mastectomy and chemoprevention. This narrative review highlights the need for understanding the genetic and epigenetic alterations in HDGLBC, which provide critical insights for developing effective therapies and improving patient outcomes. Further research is necessary to refine these strategies and explore novel therapeutic targets.