Inhibition of KIF20A enhances the immunotherapeutic effect of hepatocellular carcinoma by enhancing c-Myc ubiquitination.

Immune therapy has significantly improved the prognosis of hepatocellular carcinoma (HCC) patients, yet its efficacy remains limited, underscoring the urgency to identify new therapeutic targets and biomarkers. Here, we investigated the pathological and physiological roles of KIF20A and assess its potential in enhancing HCC treatment efficacy when combined with PD-1 inhibitors. We initially assess KIF20A's oncogenic function using liver-specific KIF20A knockout (Kif20a CKO) mouse models and orthotopic xenografts. Subsequently, we establish a regulatory axis involving KIF20A, FBXW7, and c-Myc, validated through construction of c-Myc splicing mutants. Large-scale clinical immunohistochemistry (IHC) analyses confirm the pathological relevance of the KIF20A-FBXW7-c-Myc axis in HCC. We demonstrate that KIF20A overexpression correlates with poor prognosis in HCC by competitively inhibiting FBXW7-mediated degradation of c-Myc, thereby promoting glycolysis and enhancing tumor proliferation. Conversely, KIF20A downregulation suppresses these effects, impairing tumor growth through c-Myc downregulation. Notably, KIF20A inhibition attenuates c-Myc-induced MMR expression, associated with improved prognosis in HCC patients receiving PD-1 inhibitor therapy. Furthermore, in Kif20a CKO HCC mouse models, we observe synergistic effects between Kif20a knockout and anti-PD-1 antibodies, significantly enhancing immunotherapeutic efficacy against HCC. Our findings suggest that targeting the KIF20A-c-Myc axis could identify HCC patients likely to benefit from anti-PD-1 therapy. In conclusion, we propose that combining KIF20A inhibitors with anti-PD-1 treatment represents a promising therapeutic strategy for HCC, offering new avenues for clinical development and patient stratification.

Identifying a Level of Neutralizing Antibody That Correlates With Protection From Clinical Mumps Disease During a 2017 Mumps Outbreak Among Military Service Members.

Background: In 2017, a mumps outbreak occurred in a US military barracks. Serum collected at service entry was used to compare pre-exposure with presumptive vaccine-induced antibody levels from persons who developed mumps (cases) and potentially exposed persons who did not develop mumps (non-cases). Sufficient information to determine levels of exposure during the outbreak was not available. Methods: Pre-outbreak serum samples from the Department of Defense Serum Repository were available from 254 potentially exposed service members. Twelve developed clinical symptoms and had post-outbreak serum collected. All sera were tested with a mumps-specific enzyme immunoassay for immunoglobulin M, immunoglobulin G (IgG), and IgG avidity. The neutralizing antibodies to vaccine strain (Jeryl Lynn [JL], genotype A) and wildtype virus (genotype G) was assessed by a plaque reduction neutralization test. A Fisher exact test and receiver operator characteristic curve were used to analyze the antibody response for non-cases and mumps cases. Results: Eight mumps cases were laboratory confirmed. Pre-outbreak neutralizing antibody titers to JL and genotype G mumps virus and pre-outbreak IgG index values were proportionately lower for most cases as compared with exposed non-cases. When compared with potentially exposed non-cases, cases with clinical symptoms had greater odds of having a pre-outbreak JL titer <41 and a genotype G titer <16. Conclusions: We identified potential correlates of protection for mumps neutralizing antibody titers against JL and genotype G mumps viruses.

Lynch syndrome in Mexican-Mestizo families: Genotype, phenotypes, and challenges in cascade testing among relatives at risk.

Lynch syndrome (LS) is the most frequent cancer predisposition syndrome affecting the colon and rectum. A pathogenic variant (PV) disrupting one of the mismatch repair (MMR) genes is responsible for the disease. The spectrum of tumors in LS is heterogeneous and includes cancer of the colon and rectum (CRC), endometrium, ovaries, stomach, small bowel, urinary tract, bladder, pancreas, and skin. Knowledge of the phenotypic variation of patients with LS, the type and frequency of PVs, and cascade testing studies in the Latin American population is limited. The present study aims to recognize the PVs in MMR genes, describe the phenotype in Mexican-Mestizo patients and their relatives, and identify the acceptance rate of cascade testing of relatives at risk. We included 40 carriers of a MMR gene PV and 142 relatives that developed a LS-related neoplasm. Patients' clinical data, number, and type of malignancies were obtained from their medical records. Amsterdam I-II, Bethesda criteria, and PREMM5® predictive model score were estimated. Available immunohistochemistry (IHC) reports were analyzed. Relatives at risk were determined from index cases pedigrees. The distribution of MMR gene mutations among 40 probands was: MLH1 (67.5 %), MSH2 (22.5 %), MSH6 (7.5 %), and PMS2 (2.5 %). Out of the 182 LS cases, 58 % exhibited the LS phenotype before age 50. The most common tumor was CRC, followed by endometrial cancer in women and gastric cancer in males. We found a 90.0 % concordance between the IHC and germline PV. The most frequent PV in our sample was MLH1 c.676C > T, occurring in 1/6 index cases. All probands disclosed their molecular test result to their family. Out of the 451 asymptomatic relatives at risk, 28.2 % underwent germline testing. Our results highlight the importance of conducting germline genetic studies in LS since it allows the establishment of appropriate cancer screening, risk-reducing measures, and genetic cascade testing among relatives at risk. Interestingly, we observed a significantly higher prevalence of the c.676C > T variant in MLH1, probably a singular characteristic of the Mexican-Mestizo population. New strategies to facilitate accurate communication between index cases and relatives should be implemented to improve the cascade testing acceptance rate.

Phase III, open-label, single-arm study of a new MMR vaccine (JVC-001); measles AIK-C, mumps RIT 4385, rubella Takahashi, as a second vaccine dose in healthy Japanese children aged 5-6 years.

PURPOSE: This Phase III, multicenter, open-label, single-arm study evaluated the safety and immunogenicity of the measles-mumps-rubella (MMR) combined vaccine, JVC-001, as a second MMR vaccination. METHODS: Healthy Japanese children aged 5-6 years received a single dose of JVC-001 following a first measles, mumps, and rubella vaccination (measles-rubella bivalent and mumps monovalent vaccine [Hoshino or Torii strain] or JVC-001) or the MMR vaccine received between ages 1 to <4 years. Immunogenicity was evaluated using antibody titers before and after vaccination (Day 1/Day 43). The primary endpoint was the seroprotection rate of antibody titers against each virus; geometric mean titer (GMT) was also evaluated. Adverse events (AEs) and adverse drug reactions (ADRs) were monitored. RESULTS: One-hundred participants completed the study. The seroprotection rate of antibody titers against measles, rubella, and mumps virus (genotype D) were 100.0% (95% confidence interval [CI] 96.4%, 100.0%), 100.0% (95% CI 96.4%, 100.0%), and 100.0% (95% CI 96.3%, 100.0%), respectively. GMT (fold) increases (Day 1 to Day 43) were 16.0 to 55.7 for measles virus, 35.5 to 99.0 for rubella virus, and 25.7 to 89.5 for mumps virus (genotype D). Solicited ADRs occurred in 40.0% of participants (injection site, 34.0%; systemic, 13.0%). CONCLUSIONS: The second MMR vaccination with JVC-001 demonstrated sufficient antibody coverage against all three viruses; the safety profile was tolerable. CLINICAL TRIAL REGISTRATION: jRCT2080225022.

Nationwide Real-World Data of Microsatellite Instability and/or Mismatch Repair Deficiency in Cancer: Prevalence and Testing Patterns.

Determination of microsatellite instability (MSI)/mismatch repair (MMR) status in cancer has several clinical implications. Our aim was to integrate MSI/MMR status from patients tested in Greece to assess the prevalence of MSI-high (MSI-H)/deficient MMR (dMMR) per tumor type, testing patterns over time and concordance between MSI and MMR status. We retrospectively recorded MSI/MMR testing data of patients with diverse tumor types performed in pathology and molecular diagnostics laboratories across Greece. Overall, 18 of 22 pathology and/or molecular diagnostics laboratories accepted our invitation to participate. In the 18 laboratories located across the country, 7916 tumor samples were evaluated for MSI/MMR status. MSI/MMR testing significantly increased in patients with colorectal cancer (CRC) and other tumor types overtime (p < 0.05). The highest prevalence was reported in endometrial cancer (47 of 225 patients, 20.9%). MSI-H/dMMR was observed in most tumor types, even in low proportions. Among 904 tumors assessed both for MSI and MMR status, 21 had discordant results (overall discordance rate, 2.3%). We reported MSI-H/dMMR prevalence rates in patients with diverse cancers, while demonstrating increasing referral patterns from medical oncologists in the country overtime. The anticipated high rate of concordance between MSI and MMR status in paired analysis was confirmed.

Microsatellite Instability Testing and Prognostic Implications in Colorectal Cancer.

Given the crucial predictive implications of microsatellite instability (MSI) in colorectal cancer (CRC), MSI screening is commonly performed in those with and at risk for CRC. Here, we compared results from immunohistochemistry (IHC) and the droplet digital PCR (ddPCR) MSI assay on formalin-fixed paraffin-embedded tumor samples from 48 patients who underwent surgery for colon and rectal cancer by calculating Cohen's kappa measurement (k), revealing high agreement between the methods (k = 0.915). We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression to assess the prognostic significance of ddPCR-based MSI and to identify clinicopathological features associated with CRC outcome. Patients with MSI-high had better overall survival (OS; p = 0.038) and disease-free survival (DFS; p = 0.049) than those with microsatellite stability (MSS). When stratified by primary tumor location, right-sided CRC patients with MSI-high showed improved DFS, relative to those with MSS (p < 0.001), but left-sided CRC patients did not. In multivariate analyses, MSI-high was associated with improved OS (hazard ratio (HR) = 0.221, 95% confidence interval (CI): 0.026-0.870, p = 0.042), whereas the loss of DNA mismatch repair protein MutL homolog 1 (MLH1) expression was associated with worse OS (HR = 0.133, 95% CI: 0.001-1.152, p = 0.049). Our results suggest ddPCR is a promising tool for MSI detection. Given the opposing effects of MSI-high and MLH1 loss on OS, both ddPCR and IHC may be complementary for the prognostic assessment of CRC.

All three MutL complexes are required for repeat expansion in a human stem cell model of CAG-repeat expansion mediated glutaminase deficiency.

The Repeat Expansion Diseases (REDs) arise from the expansion of a disease-specific short tandem repeat (STR). Different REDs differ with respect to the repeat involved, the cells that are most expansion prone and the extent of expansion. Furthermore, whether these diseases share a common expansion mechanism is unclear. To date, expansion has only been studied in a limited number of REDs. Here we report the first studies of the expansion mechanism in induced pluripotent stem cells derived from a patient with a form of the glutaminase deficiency disorder known as Global Developmental Delay, Progressive Ataxia, And Elevated Glutamine (GDPAG; OMIM# 618412) caused by the expansion of a CAG-STR in the 5' UTR of the glutaminase (GLS) gene. We show that alleles with as few as ~ 120 repeats show detectable expansions in culture despite relatively low levels of R-loops formed at this locus. Additionally, using a CRISPR-Cas9 knockout approach we show that PMS2 and MLH3, the constituents of MutLα and MutLγ, the 2 mammalian MutL complexes known to be involved in mismatch repair (MMR), are essential for expansion. Furthermore, PMS1, a component of a less well understood MutL complex, MutLß, is also important, if not essential, for repeat expansion in these cells. Our results provide insights into the factors important for expansion and lend weight to the idea that, despite some differences, the same mechanism is responsible for expansion in many, if not all, REDs.

TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complimentary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 hr treatment of 10µM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS affected neurons.

Shedding of measles vaccine RNA in children after receiving measles, mumps and rubella vaccination.

BACKGROUND: Measles, mumps, and rubella(MMR) vaccination is critical to measles outbreak responses. However, vaccine reactions and detection of measles vaccine RNA in recently immunized persons may complicate case classification especially in those presenting with another respiratory viral illness. We aim to characterize cases of measles vaccine shedding in recently vaccinated children presenting with respiratory viral symptoms. METHODS: Children who were tested with a multiplex respiratory panel <30 days after receiving MMR were identified. Remnant nasopharyngeal(NP) samples were tested for measles vaccine by PCR. Medical records were reviewed for demographics, presenting symptoms, and test results. RESULTS: From January 2022 to March 2023, 127 NP from children who received MMR were tested. Ninety-six NP were collected after the first dose, of which 33(34.4 %) were positive for vaccine RNA. The median interval between MMR and detection was 11.0 days. Thirty-one NP were collected after the second MMR and 1(3.2 %) was positive; time between the vaccination and detection was 18.9 days. Median cycle threshold(Ct) value of the measles PCR for vaccine shedding was significantly higher than median Ct in children with wild-type infection. CONCLUSION: Shedding of measles vaccine RNA is not uncommon and vaccine RNA can be detected up to 29 days post MMR; the amount of vaccine RNA shedding is low indicated by high Ct values. Clinicians and public health officials should consider performing measles vaccine testing on those testing positive for measles within one month of MMR vaccination, especially if the Ct value is high and definitive epidemiological links are absent.

TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 µM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.

Demystifying the Mystery of Genes: A Case Report on Constitutional Mismatch Repair Deficiency.

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6, or PMS2. This syndrome is characterized by a broad spectrum of early-onset malignancies, including hematologic malignancies, colorectal malignancies, brain tumors, and other malignancies. It is common to have more than one malignancy in an individual diagnosed with CMMRD. In addition to malignancies, primary immunodeficiency in the form of low or absent immunoglobulin levels can also be seen in CMMRD. Congenital abnormalities such as agenesis of the corpus callosum (ACC), cavernous hemangioma, and other non-neoplastic diseases can also be linked to it. In this case report, we discussed the case of a girl born out of consanguineous marriage initially identified as having T-cell acute lymphoblastic lymphoma and later found to have selective immunoglobulin A (IgA) deficiency. Her younger sibling with a pontine cavernous hemangioma was also diagnosed with lymphoma. The girl exhibited brain lesions on magnetic resonance imaging (MRI), which were initially diagnosed as posterior reversible encephalopathy syndrome (PRES) related changes; however, one of the lesions persisted and remained stable over a period of 2 years and more in favor of diffuse glioma. The younger sibling also showed a solitary lesion in the brain. Based on the clinical and radiological findings, a diagnosis of CMMRD was suspected. Next-generation sequence (NGS) analysis of her blood sample was done. The results showed a homozygous mutation in the MSH6 gene was diagnostic of CMMRD.

The Case for Assessing the Drivers of Measles Vaccine Uptake.

Global measles cases are on the rise following disruptions to routine immunisation programs during the COVID-19 pandemic, with devastating consequences. According to the World Health Organization, the behavioural and social drivers of vaccination include what people think and feel about vaccines, social processes, motivation to vaccinate and practical barriers to vaccination. However, the drivers of measles vaccine uptake are not necessarily the same as those for other childhood vaccines, and we lack data on how these drivers specifically have changed during and since the COVID-19 pandemic. Without accurately measuring the behavioural and social drivers for measles vaccination, and ideally measuring them serially over time, countries cannot design, target and implement interventions that effectively increase and sustain measles vaccine coverage. This paper outlines what is and is not known about the behavioural and social drivers of measles vaccination and provides recommendations for improving their post-pandemic assessment.

"If the nurse tells me this is a good thing, I trust her completely" - Exploring health system enablers of MMR vaccine uptake in the Finnish Somali community: A mixed method study.

BACKGROUND: Globally, migrant populations usually experience lower vaccine coverage than the general population. In Finland, the MMR vaccination coverage of Somalis has not been studied specifically, but existing evidence suggests that the MMR vaccination coverage is high. The aim of this study was to examine both vaccination coverage of Somali children and factors associated with the MMR vaccine uptake of Somali children living in Finland. METHODS: Twenty-seven mothers and seventeen public health nurses were interviewed using a semi-structured interview protocol. Audio-recorded interviews were transcribed and translated and analysed thematically after coding. The personal identity code of Somali children born in 2015 and 2020 were extracted from the Population Information System (PIS), and their vaccination coverage data was extracted from the national vaccination register (NVR) to calculate MMR vaccination coverage for Somali children. RESULTS: 96 % of Somali children born in 2015 and 81 % of those born in 2020 received their MMR vaccination. In contrast, the national average MMR vaccine uptake for children born in 2015 was 95 %, while 94 % of those born in 2020 were vaccinated against MMR. Somali mothers had poor knowledge of the MMR vaccine and the diseases it protects against. Trust towards the Finnish healthcare system, perceived benefits of vaccinating, positive attitudes towards vaccines, nurses' systematic approach to vaccine introduction, and nurses taking into account the cultural background of the clients were recognised as enablers positively affecting MMR vaccination uptake. CONCLUSION: Despite limited knowledge of vaccines, Somali immigrant mothers believe in the benefits of vaccination, and they displayed strong trust towards public health nurses. Further investigation is needed to understand why MMR vaccination coverage has declined among the younger Somali population.

Seroepidemiology of measles and rubella among Hong Kong young adults and the humoral responses of an MMR booster among participants with low antibody levels.

BACKGROUND: Some individuals may not retain adequate immunity against measles and rubella years after two doses of measles, mumps, and rubella (MMR) vaccination due to vaccine failure. This study aimed to investigate the rates of vaccine failure and seroconversion by administering an MMR booster to young adults. METHODS: We first assessed measles and rubella antibody levels using the Luminex multiplex assay, VIDAS IgG assay, and plaque reduction neutralization test (PRNT) among individuals aged 18-30 years old who had received two doses of MMR vaccine. Participants with low measles and/or rubella antibody levels as confirmed by VIDAS received an MMR booster. Antibody levels were measured at 1-month post-booster. RESULTS: Among 791 participants, the measles and rubella seroprevalence rates were 94.7% (95% CI: 92.9%-96.0%) and 97.3% (95% CI: 96.0%-98.3%), respectively. Lower seroprevalence rates were observed among older participants. 113 participants who received an MMR booster acquired higher measles and rubella antibody levels at 1-month post-booster compared to baseline. CONCLUSIONS: Although measles and rubella vaccine failures were observed among 5.3% and 2.7% of young adults, respectively, an MMR booster triggered a significant antibody response.

Cost-Effectiveness Analysis of Routine Outreach and Catch-Up Campaign Strategies for Measles, Mumps, and Rubella Vaccination in Chuuk, Federated States of Micronesia.

OBJECTIVE: The Federated States of Micronesia (FSM) experience periodic outbreaks of vaccine-preventable diseases. Our objective was to assess the cost-effectiveness of routine outreach and catch-up campaign strategies for increasing vaccination coverage for the measles, mumps, and rubella (MMR) vaccine among children aged 12 months through 6 years in Chuuk, FSM. METHODS: We used a cost-effectiveness model to assess 4 MMR vaccination strategies from a public health perspective: routine outreach conducted 4 times per year (quarterly routine outreach), routine outreach conducted 2 times per year (biannual routine outreach), catch-up campaigns conducted once per year (annual catch-up campaign), and catch-up campaigns conducted every 2 years with quarterly routine outreach in non-catch-up campaign years (status quo). We calculated costs and outcomes during a 5-year model horizon and summarized results as incremental cost-effectiveness ratios. We analyzed the following public health outcomes: additional protected person-month (PPM), doses administered and protected people (ie, a child who completed a 2-dose MMR series). We conducted 1-way sensitivity analyses to evaluate the stability of incremental cost-effectiveness ratios and to identify influential model inputs. RESULTS: Among the 4 MMR vaccination strategies, quarterly routine outreach was the most effective and most expensive strategy, and biannual routine outreach was the least expensive and least effective strategy. Quarterly routine outreach (vs status quo) yielded approximately an additional 7001 PPMs and 132 vaccine doses administered, with incremental costs of about $4 per PPM, $193 per dose administered, and $123 per protected person. CONCLUSION: Routine outreach and catch-up campaign vaccination strategies can be important interventions to improve health in Chuuk, FSM. More frequent routine outreach events could improve MMR coverage and reduce the likelihood of outbreaks of vaccine-preventable diseases such as measles and mumps.

Treatment of Microsatellite-Unstable Rectal Cancer in Sporadic and Hereditary Settings.

Microsatellite instability is rare in rectal cancer and associated with younger age of onset and Lynch syndrome. All rectal cancers should be tested for microsatellite instability prior to treatment decisions. Patients with microsatellite instability are relatively resistant to chemotherapy. However, recent small studies have shown dramatic response with neoadjuvant immunotherapy. Patients with Lynch syndrome have a hereditary predisposition to cancer and thus an elevated risk of metachronous cancer. Therefore, while "watch and wait" is a well-established practice for sporadic rectal cancers that obtain a complete clinical response after chemoradiation, its safety in patients with Lynch syndrome has not yet been defined. The extent of surgery for patients with Lynch syndrome and rectal cancer is controversial and there is significant debate as to the relative advantages of a segmental proctectomy with postoperative endoscopic surveillance versus a therapeutic and prophylactic total proctocolectomy. Surgical decision making for the patient with Lynch syndrome and rectal cancer is complex and demands a multidisciplinary approach, taking into account both patient- and tumor-specific factors. Neoadjuvant immunotherapy show great promise in the treatment of these patients, and further maturation of data from prospective trials will likely change the current treatment paradigm. Patients with Lynch syndrome and rectal cancer who do not undergo total proctocolectomy require yearly surveillance colonoscopies and should consider chemoprophylaxis with aspirin.

Family history as a major prerequisite for microsatellite instability screening in colorectal cancer is a poor selection tool.

Background: Deficient mismatch repair (MMR) leading to microsatellite instability (MSI) in tumors is thought to be present in over 15% of colorectal cancer (CRC) cases. Testing CRC for MSI has traditionally been recommended following the fulfillment of clinical criteria. However, the performance of clinical criteria, especially the family history, as a selection tool for MSI screening in CRC is questionable. Methods: We retrospectively investigated the incidence of high degree MSI (MSI-H) tumors in an unselected population of CRC patients and compared its prevalence between individuals with and without family history of cancers within the spectrum of MSI-H tumors as defined in the revised Bethesda criteria. Results: The study population included 274 patients, 70 with positive and 204 without family history of MSI-H tumors with complete data including findings from MSI analysis. The overall incidence of MSI-H CRC was 18.98%. There was no statistically significant difference in the incidence of MSI-H CRC amongst both groups. The sensitivity and specificity of family history with regard to the presence of an MSI-H tumor in this collective was 36.5% and 77.5%, respectively. Conclusions: A relevant number of cases with high MSI-H CRC may be missed secondary to screening based on clinical criteria like family history alone. Thus, systematic screening independent of clinical characteristics, especially family history of cancer should be recommended in all cases with CRC.

Immunity against measles, mumps, rubella, and varicella among homeless individuals in Germany - A nationwide multi-center cross-sectional study.

Introduction: Homeless individuals suffer a high burden of vaccine-preventable infectious diseases. Moreover, they are particularly susceptible to adverse infection outcomes with limited access to the health care system. Data on the seroprevalence of measles, mumps, rubella, and varicella within this cohort are missing. Methods: The seroprevalence of measles, mumps, rubella, and varicella was determined within the homeless population in Germany. Predictors of lacking immune protection were determined using multivariable logistic regression analysis. Results: Homeless individuals in Germany (n = 611) showed a seroprevalence of 88.5% (95% CI: 85.8-91.0) for measles, 83.8% (95% CI: 80.6-86.6) for mumps, 86.1% (95% CI: 83.1-88.7) for rubella, and 95.7% (95% CI 93.8-97.2) for varicella. Measles seroprevalences declined from individuals born in 1965 to individuals born in 1993, with seroprevalences not compatible with a 95% threshold in individuals born after 1980. For mumps, seroprevalences declined from individuals born in 1950 to individuals born in 1984. Here, seroprevalences were not compatible with a 92% threshold for individuals born after 1975. Seronegativity for measles, mumps and rubella was associated with age but not with gender or country of origin. Discussion: Herd immunity for measles and mumps is not achieved in this homeless cohort, while there was sufficient immune protection for rubella and varicella. Declining immune protection rates in younger individuals warrant immunization campaigns also targeting marginalized groups such as homeless individuals. Given that herd immunity thresholds are not reached for individuals born after 1980 for measles, and after 1975 for mumps, vaccination campaigns should prioritize individuals within these age groups.

RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.

TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Raising Epidemiological Awareness: Assessment of Measles/MMR Susceptibility in Highly Vaccinated Clusters within the Hungarian and Croatian Population-A Sero-Surveillance Analysis.

Perceptions of the complete eradication of vaccine-preventable diseases such as measles, mumps, and rubella (MMR) may foster complacency and compromise vaccination efforts. Decreased measles vaccination rates during the COVID-19 pandemic have heightened the risk of outbreaks, even in adequately vaccinated populations. To address this, we have aligned with ECDC recommendations, leveraging previous cross-border sero-epidemiological assessments between Pécs, Hungary, and Osijek, Croatia, to identify latent risk groups and uncover potential parallels between our nations. Testing 2680 Hungarian and 1764 Croatian serum samples for anti-MMR IgG via ELISAs revealed anti-measles seropositivity ratios below expectations in Croatian cohorts aged ~20-30 (75.7%), ~30-40 (77.5%) and ~40-50 years (73.3%). Similarly, Hungarian samples also showed suboptimal seropositivity ratios in the ~30-40 (80.9%) and ~40-50 (87.3%) age groups. Considering mumps- and rubella-associated seropositivity trends, in both examined populations, individuals aged ~30-50 years exhibited the highest vulnerability. Additionally, we noted congruent seropositivity trends across both countries, despite distinct immunization and epidemiological contexts. Therefore, we propose expanding research to encompass the intricate dynamics of vaccination, including waning long-term immunity. This understanding could facilitate targeted interventions and bolster public awareness. Our findings underscore persistent challenges in attaining robust immunity against measles despite vaccination endeavors.