Search Results (724)

Objectives: Endometrial cancer is the most common gynaecologic malignancy, and its mortality rate is rising. Advanced or recurrent disease remains challenging because historically there have been limited therapeutic options. We aim to describe a complete and durable response to the HER2-directed antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in a heavily pretreated patient with HER2-positive, mismatch-repair-deficient metastatic serous endometrial cancer. Methods: A 72-year-old woman underwent hysterectomy, bilateral salpingo-oophorectomy, and staging procedures for FIGO stage IIIA, high-grade serous papillary endometrial carcinoma. Tumour profiling revealed dMMR, a p53 abnormal pattern, and HER2 overexpression (IHC 3+). She received carboplatin/paclitaxel plus avelumab, followed by pegylated liposomal doxorubicin and weekly paclitaxel. After progression on paclitaxel, off-label T-DXd was initiated. Molecular data (FoundationOne CDx) were collected, along with and serial imaging and CA125 assessments. Results: The patient developed cough after two cycles of T-DXd; interstitial lung disease was excluded, and treatment resumed with steroid cover. By December 2024, PET/CT demonstrated complete metabolic response, with resolution of vaginal-vault and para-aortic lesions and normalisation of CA125. Real-world progression-free survival exceeded eight months, with ongoing symptom improvement. Treatment was generally well tolerated; the principal adverse event was grade 3 neutropenia requiring dose reduction. No cardiotoxicity or interstitial lung disease occurred. Conclusions: This case illustrates that T-DXd can induce deep and durable remission in HER2-positive, dMMR metastatic serous endometrial cancer after multiple lines of therapy. It adds real-world evidence supporting further investigation of HER2-directed antibody–drug conjugates in gynaecologic malignancies, and underscores the need for confirmatory trials and refined biomarker-driven patient selection. Full article

Mismatch repair (MMR) system alterations can trigger transient hypermutation, promoting adaptive mutations under stress, such as antibiotic exposure. While most organisms use MutS and MutL protein families for MMR, many archaea and actinobacteria, including the major human pathogen Mycobacterium tuberculosis, lack these components and instead rely on NucS, a structurally distinct enzyme driving a non-canonical MMR pathway. Given the role of MMR in mutation control, understanding how nucS expression is regulated could be essential for uncovering the molecular basis of antibiotic resistance development in mycobacteria. In this study, we characterized the nucS promoter and transcription start site in Mycobacterium smegmatis. We found that nucS expression declines during the stationary phase in both M. smegmatis and M. tuberculosis, paralleling replication activity and canonical MMR downregulation. Our data suggest that the alternative sigma factor σ^B may negatively regulate nucS expression during this phase. Additionally, we identified candidate compounds that may modulate nucS expression, underscoring its responsiveness to environmental cues. These findings enhance our understanding of mycobacterial stress responses and lay the groundwork for exploring antibiotic resistance mechanisms. Strikingly, our work reveals a case of double convergent evolution: both canonical (MutS/MutL) and non-canonical (NucS) pathways have independently evolved not only the same DNA repair function, but also similar regulatory frameworks for genome integrity preservation under stress conditions. Full article

This paper presents an innovative approach to efficiently harvesting energy from ocean waves through a buoy-type Wave Energy Converter (WEC). The proposed methodology integrates a buoy, a Mechanical Motion Rectifier (MMR), a Motion Rectifier (MR), an Energy Storage Element (ESE), and an electric generator. A MATLAB-2023 model has been employed to assess the electrical power generated under varying wave heights and frequencies. Experimental data and numerical simulations reveal that the prototype Wave Energy Harvester (WEH) achieved a peak voltage of 6.7 V, peak power of 3.6 W, and an average power output of 8.5 mW, with an overall efficiency of 47.2% for the device’s actual size. Additionally, a theoretical analysis has been conducted to investigate the impact of incorporating additional buoys on the electrical power output. Full article

Background/Objectives: Colorectal neuroendocrine carcinomas (NECs) are rare, aggressive tumors with poorly defined clinicopathologic and molecular features. Their biological behavior and optimal treatment strategies remain unclear. Additionally, a subset of anorectal NECs may be associated with high-risk human papillomavirus (HPV) infection, suggesting potential heterogeneity in pathogenesis. Methods: We retrospectively reviewed 12 cases of colorectal NECs. Clinical outcomes, histologic morphology, immunohistochemistry, molecular profiling, including common oncogenic mutations, and HPV status were analyzed. Results: Seven cases demonstrated small cell NECs, and five showed large cell NECs. The majority of NECs (n = 9) arose in the rectum. TP53 mutations were the most common (75%), followed by KRAS, RB1, FBXW7, and BRAF mutations. One case demonstrated mismatch repair (MMR) deficiency. High-risk HPV was detected in one rectal NEC, which lacked common oncogenic mutations and was the only long-term survivor (54 months). p16 expression did not correlate consistently with HPV in situ hybridization (ISH) status. Among small cell NECs with follow-up, platinum-based chemotherapy resulted in significantly longer survival than FOLFOX (13.5 vs. 4 months, p = 0.0209). Conclusions: Colorectal NECs display histologic and molecular heterogeneity. The tumors of small cell NECs potentially benefit more from platinum-based chemotherapy. HPV-associated NECs may represent a distinct subset with better prognosis, but p16 is not a reliable surrogate marker. Routine subclassification into small vs. large cell types and comprehensive molecular profiling, including HPV testing, may aid clinical decision-making and prognostication. Full article

Background and Objectives: Measles is a highly contagious but vaccine-preventable disease with significant morbidity in the European region, including Romania, especially in the post-COVID-19 era with low vaccination rates which no longer provide herd immunity. The current study aims to show how vaccination reduces the disease burden. Methods: A study using 29,148 cases with measles-compatible features in Romania from the 2020–2024 period was performed, analyzing symptoms, complications, and hospitalization rates comparatively between vaccinated and non-vaccinated groups. Results: Our findings show substantial hospitalization rates reduction among vaccinated cases with an over 12% decrease—depending on the number of MMR doses—as well as reduced severity of clinical features, but no significant effect on disease duration. Conclusions: MMR vaccination provides protection beyond primary disease prevention, as it reduces the disease burden among measles cases by reducing disease-related hospitalizations and improving clinical outcomes. Full article

The interlaminar drilling of CFRPs is a new machining method different from traditional drilling, in which the feed direction of the drill bit is parallel to the interlayer interface. To reasonably select tools for CFRP interlaminar drilling, four different types of tool structures, including twist drills, dagger drills, candlestick drills, and step drills, are employed to conduct interlaminar drilling. The axial force and the morphologies of material damage are extracted, the comprehensive damage factors are calculated, and the relation among tool structures, machining parameters, and outlet damage is analyzed. Results show that the peak axial force induced by the four types of tool structures reduces sequentially. The dagger drill and the candlestick drill tend to cause burrs and large-area surface tears, respectively, while the twist drill and the step drill will lead to more significant 3D tears. Among the four tools, the average comprehensive damage factor produced by twist drills is the smallest, making it more suitable for CFRP interlaminar drilling. In addition, this study establishes a mathematical prediction model for the peak axial force and the comprehensive damage factor and optimizes the process parameter combination of twist drills, with the spindle speed set to 4732.87 r/min and the feed speed to 0.137 mm/r. Full article

Universal tumor screening (UTS) of all newly diagnosed colorectal cancers (CRCs) for the identification of Lynch syndrome (LS) is recommended. We explored the impact of the COVID-19 pandemic on the UTS process in a safety-net university hospital to identify areas of vulnerability and opportunities for improvement. Patients undergoing resection of a primary CRC were categorized into three cohorts based on surgery date relative to the pandemic (pre-[2018,2019], early-[2020,2021] and late-[2022]). Data regarding (1) UTS performance of immunohistochemistry (IHC) for LS genes and microsatellite instability (MSI) testing; (2) referrals to cancer genetic counseling (CGC) based on mismatch repair deficient (dMMR) status and/or age < 50 years at diagnosis; (3) attendance at CGC; and (4) reasons for not attending CGC were extracted. Between 2018 and 2022, 342 patients underwent resection of a CRC. During the three time periods (pre-, early- and late-pandemic), 93%, 94% and 96% of cases were screened with at least MMR IHC, respectively. Of the patients eligible for referral to CGC in each time period, 60%, 71% and 63% had a referral submitted. Of these, 23%, 36% and 20% in each time period did not attend CGC, with the most common reason for not attending being the inability of schedulers to reach the patient. Although the COVID-19 pandemic did not cause significant variation in the different steps of the UTS process, CGC utilization remained suboptimal throughout the three time periods. Further research on barriers preventing physicians from referring patients to CGC as well as schedulers inability to reach eligible patients should be pursued. Full article

Background: Deficient mismatch repair rectal cancer represents approximately 10% of rectal malignancies and demonstrates exceptional responsiveness to immune checkpoint inhibitors, achieving unprecedented complete response rates approaching 100%. This creates a novel clinical dilemma: should patients achieving complete response undergo standard surgical resection or pursue organ preservation through watch-and-wait management? Methods: We conducted a comprehensive literature review of clinical trials and retrospective studies published through 2025, focusing on response assessment strategies, decision-making frameworks, oncological outcomes, and quality of life assessments. Results: Landmark studies demonstrated remarkable efficacy with dostarlimab achieving 100% clinical complete response, while surgical cohorts achieved 68–92% pathological complete response rates. Response assessment challenges included pseudoprogression and pseudoresidue phenomena that complicated conventional imaging interpretation and required specialised multimodal evaluation protocols. Comparative analyses suggest equivalent oncological outcomes between surgical and non-surgical approaches in complete responders, achieving 100% disease-free survival at 2–3 years across multiple studies. The watch-and-wait approach offered significant advantages by preserving organ integrity and avoiding surgical morbidity, including permanent colostomy (15.4%) and perioperative complications (19.3%). Conversely, surgical management provided distinct benefits through definitive tissue confirmation and anxiety relief from intensive surveillance requirements and potential recurrence concerns. Conclusions: The surgery versus watch-and-wait dilemma represents a choice between equally effective oncological approaches with different quality of life implications. Evidence supports individualised decision-making weighing functional preservation benefits against patient preferences and institutional capabilities in this evolving therapeutic landscape. Full article

MSI-H/dMMR endometrial cancer (EC) is closely linked to the mismatch repair (MMR) pathway, and its pathogenesis is associated with microsatellite instability (MSI) caused by abnormalities in the core genes of the conventional MMR system. This cancer exhibits a distinct immune microenvironment, which makes it suitable for treatment with immune checkpoint inhibitors (ICIs). This cancer type demonstrates heterogeneity, encompassing Lynch syndrome (LS)-associated EC (characterized by germline mutations), sporadic EC (attributed to MLH1 promoter hypermethylation), and Lynch-like EC (driven by somatic mutations). Research indicates that these three dMMR EC subtypes possess different immune microenvironments, which may influence the therapeutic efficacy of ICIs. However, the impact of somatic mutations in traditional MMR genes on EC has often been overlooked. Furthermore, over 50% of patients with MSI exhibit no response to ICIs, potentially due to abnormalities in nontraditional MMR genes. This review discusses the role of traditional and nontraditional MMR genes in dMMR EC and related treatment strategies, highlights key issues in the current diagnosis and treatment of dMMR EC, and aims to enhance understanding of its heterogeneity and advance precision diagnosis and treatment. Full article

The mismatch repair system is critical for correcting base–base mismatches and insertion-deletion loops during DNA replication. Deficiencies in MMR (due to mutations in MLH1, MSH2, MSH6, or PMS2) lead to microsatellite instability and contribute to the development of various cancers, such as Lynch syndrome-related colorectal cancer and sporadic tumors. This review will delve into the molecular basis of MMR deficiency. Additionally, the review will cover diagnostic approaches for detecting MSI and MMR deficiency, including next-generation sequencing and PCR-based methods. The implications for treatment will be discussed, emphasizing immune checkpoint inhibitors (e.g., pembrolizumab) that target tumors with high mutational burdens due to MMR deficiency, as well as novel therapeutic approaches like synthetic lethality exploiting DNA repair vulnerabilities. Full article

Measles exposures have historically been rare since the introduction of routine vaccination programs, resulting in a lack of attention from cancer patients, hematopoietic stem cell transplant (HCT) recipients, patients receiving cellular therapy (CT) and their healthcare providers. It is essential to acknowledge the importance of vigilance in these situations. Measles herd immunity has declined significantly in North America due to rising vaccine hesitancy, resulting in outbreaks. Measles can result in severe outcomes, and its reemergence has raised alarm among patients and healthcare professionals caring for HCT/CT recipients. Patients with severe immunocompromising conditions cannot receive live-attenuated vaccines, such as the measles vaccine. The lack of data on measles prevention in this vulnerable group presents significant clinical challenges. In response, Cell Therapy Transplant Canada (CTTC) Infectious Diseases Working Committee has developed a set of frequently asked questions to provide expert guidance to HCT and CT recipients, acknowledging the limited evidence base. Full article

Endometrial cancer represents one of the most common gynecological cancers in women. In recent years, there has been increasing interest in immunotherapy, including the use of pembrolizumab, particularly for the treatment of cancers with deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H). A systematic review of the literature from 2020 to 2025 was conducted according to the PICO model. Six studies were included in this review, comprising four randomized clinical trials (RCTs) and two pre-specified subgroup analyses derived from previous RCTs involving a total of 3684 patients with early-stage or advanced disease or metastatic or recurrent endometrial cancer. Interventions included the use of pembrolizumab in monotherapy and in combination with chemotherapy or lenvatinib. Pembrolizumab showed a significant improvement in progression-free survival (PFS) and overall survival (OS) in the dMMR patient groups. Therapeutic benefit was limited in the proficient mismatch repair (pMMR) groups. The incidence of side effects was high but comparable to the control group. Pembrolizumab, especially in combination therapy with lenvatinib, is a promising therapeutic option for patients with dMMR/MSI-H endometrial cancer. The results suggest a potential long-term treatment effect, although the limitations of the RCT and the variability in the therapeutic regimens require further research. Full article

Background: High national MMR coverage in Saudi Arabia coexists with sporadic measles, mumps, and rubella cases. Local data are needed to describe vaccination coverage among the reported cases and patterns of laboratory-confirmed infections. Objectives: This study was conducted to describe MMR vaccination coverage among the reported suspected cases and patterns of laboratory-confirmed measles, mumps, and rubella in Al-Baha, Saudi Arabia, from January 2020 to August 2024, and to examine associations between demographics, residence, vaccination status, and case classification. Methods: We conducted a retrospective analysis of surveillance records from the Al-Baha Communicable Disease Reporting System. We summarized the demographics, vaccination history, and final classification for 295 reported suspected cases. Inferential analyses (chi-square and logistic regression) used laboratory-confirmed cases only. Statistical significance was p < 0.05. Results: Of 295 reported suspected cases, 239 (81.0%) were discarded after investigation, and 52 (17.6%) were confirmed (including 50 laboratory-confirmed and two epidemiologically confirmed), with 3 (1.0%) remaining under review at analysis. Among all reported cases, the vaccination status was ≥2 doses, 57.6% (n = 170), one dose, 19.0% (n = 56), and unvaccinated/unknown, 23.4% (n = 69). Among the laboratory-confirmed infections, measles was clustered in unvaccinated/unknown, mumps was clustered in single-dose recipients, and rubella was in ≥2-dose recipients. In multivariable models, males had higher odds of a laboratory-confirmed infection, and rural residence was associated with increased odds. The confidence intervals were wide due to small numbers. Conclusions: Reported surveillance data show persistent laboratory-confirmed MMR infections in Al-Baha with demographic and geographic disparities. The findings support targeted efforts to complete two-dose schedules, strengthen rural access, and improve immunization record systems. The results are associations and not causal measures of vaccine effectiveness, and should be interpreted in light of small confirmed case counts. Full article

A mutation detection strategy based on mismatch digestion was applied previously in barley seedlings carrying the chloroplast mutator (cpm) genotype through many generations. Sixty-one mutations were detected along with four large indels: a 15 bp insertion in the intergenic region between tRNA^His and rps19 genes, a 620 bp deletion in the psbA gene, a 79 bp deletion in the intergenic region between rpl33 and rps18 genes and a 45 bp deletion in the rps3 gene. The present investigation aims to understand the mechanisms producing the large indels and to better characterize the cpm mutagenic effect. Whole plastome sequencing revealed novel polymorphisms that were identified either in regions not previously examined or in regions that were explored but not detected through celery juice extract (CJE) digestion. The 620 bp deletion in the psbA gene was lethal when homoplastomic, whereas the 45 bp deletion in the rps3 gene did not affect the viability of the seedlings even in homoplastomy. The presence of direct repeats at the borders of large indels suggests that they could have originated by illegitimate recombination because of CPM protein malfunction. A truncated mismatch repair MSH1 protein identified in cpm seedlings suggests that CPM is involved in organellar genome stability maintenance. Full article

Background: Recent studies highlight the role of microsatellite instability (MSI) in tumor progression. This study examines the link between MSI, type of loss of function, and disease progression in low-grade endometrial carcinoma clinically confined to the uterus, focusing on myometrial infiltration. Materials and Methods: This retrospective case-control study analyzed data from 144 women treated for clinical stage I low-grade endometrial carcinoma at two university hospitals. Patients were divided into two groups based on microsatellite status: 118 with microsatellite stability (MSS) and 26 with MSI. Immunohistochemical profiling assessed MMR proteins (MLH1, PMS2, MSH2, MSH6). The primary outcome was the presence of myometrial infiltration, and the secondary outcome was the deepness of infiltration. Data were statistically analyzed using Fisher’s exact, Chi-square, and Wilcoxon tests, with logistic regression applied to evaluate the impact of MSI on these outcomes. Results: Myometrial infiltration was present in 96% of MSS and 98% of MSI cases (p = 0.5). However, deep infiltration (≥50%) was more frequent in patients with MSI (38% vs. 19%, p = 0.042). Stratification by heterodimer loss revealed that loss of MLH1/PMS2 was associated with a higher rate of deep infiltration (47%), while loss of MSH2/MSH6 correlated with lower infiltration risk (14%). In multivariate analysis, MSH2/MSH6 loss remained negatively associated with infiltration (OR 0.88; 95% CI 0.80–0.98; p = 0.020), independent of grade and LVSI. Conclusions: In low-grade endometrial carcinomas clinically confined to the uterus, MSI does not increase the overall prevalence of myometrial infiltration but is associated with deeper invasion, especially in cases with MLH1/PMS2 loss. MSI profiling could aid in risk stratification and therapeutic planning, particularly in candidates for fertility-sparing treatment. Full article