The incidence of cancer in humans has been rising in association with extended life spans. Incidence rates of early onset cancers in humans <55 years of age have also been increasing for unclear reasons. One potential contributory factor is an antagonistic pleiotropy in which certain genes that appeared in mammals to increase fitness for reproduction contribute to cancer susceptibility later in life. A related concept is an evolutionary mismatch in which humans have adapted to certain environmental and dietary factors that change over time and thereby increase cancer incidence. The MUCIN 1 (MUC1) gene emerged in mammals and represents an example of antagonistic pleiotropy and evolutionary mismatch that is posited here as a contributing factor to the increasing incidence of cancer in humans. This Review focuses on the roles of MUC1 and the oncogenic M1C protein in reproductive fitness and barrier tissue protection that in settings of chronic inflammation promote pan-cancer progression and treatment resistance. Also highlighted are therapeutic approaches targeting MUC1 and M1C that are under clinical and pre-clinical development.
Publications by Year: 2026
2026
BACKGROUND: Rotator cuff repair (RCR) is increasingly performed due to advancements in surgical techniques and an aging population. While generally successful, complications like re-tear, stiffness, infection, and thromboembolic events remain concerns. The rising use of testosterone replacement therapy (TRT) in middle-aged and older men raises questions about its impact on surgical outcomes, as its effect on RCR complications remains unclear.
METHODS: A retrospective cohort study was conducted using the PearlDiver Database. Patients who underwent arthroscopic RCR between January 2010 and April 2023 were identified using Current Procedural Terminology code 29827. Those with at least two years of continuous follow-up were included, while patients under 21 or with unknown procedural laterality were excluded. Patients were categorized into 2 cohorts: those who received TRT within three months preoperatively and a control group who did not. Propensity score matching (1:1, caliper = 0.001) was performed to control for age, gender, Charlson Comorbidity Index, obesity, tobacco use, and hypogonadism. The primary outcomes included 2-year postoperative complications and reoperations. Secondary outcomes included 90-day major medical complications such as surgical site infection, pneumonia, pulmonary embolism, deep vein thrombosis, urinary tract infection, wound dehiscence, sepsis, acute kidney injury, and readmissions. Statistical analyses were performed using chi-square tests, and odds ratios with 95% confidence intervals were calculated.
RESULTS: A total of 8,241 TRT users and 673,982 control patients were identified before matching. After propensity score matching, 5,109 patients remained in each cohort with no significant baseline differences. No significant differences were observed in 90-day postoperative complications, including surgical site infection (0.5% vs. 0.4%, P = .64), pneumonia (0.6% vs. 0.5%, P = .79), sepsis (0.4% vs. 0.3%, P = .51), acute kidney injury (0.7% vs. 0.5%, P = .18), or readmissions (1.2% vs. 1.0%, P = .29). Similarly, no significant differences were found in pulmonary embolism or deep vein thrombosis. Over the 2-year follow-up, TRT use was associated with a higher incidence of total shoulder arthroplasty (0.7% vs. 0.4%, P = .037) but a lower incidence of lysis of adhesions (0.5% vs. 0.9%, P = .032). No significant differences were observed in revision RCR rates (2.6% vs. 2.3%, P = .41).
CONCLUSION: Preoperative TRT use was not linked to increased short-term complications after arthroscopic RCR. Over two years, TRT was associated with higher rates of total shoulder arthroplasty but lower rates of lysis of adhesions, with no difference in revision RCR.
The 277th ENMC workshop on Congenital Myopathies was held in Amsterdam, The Netherlands, on 21-23 June, with 26 clinical, research, and curation experts and patient representatives from five continents. The workshop aimed to 1) establish an updated nomenclature and 2) update recommendations for their diagnostic evaluation. It was agreed that the preferred acronym for congenital myopathies is CMYO. Consensus defined CMYOs as a heterogeneous group of genetic muscle disorders typically presenting perinatally or in infancy with hypotonia and muscle weakness, usually non- or slowly progressive, with distinctive structural, non-dystrophic histopathological features. A nomenclature framework integrating gene, mode of inheritance, and histopathology was proposed, exemplified by "autosomal recessive RYR1-congenital myopathy with cores." Diagnostic consensus emphasized a genetics-first approach, using targeted massively parallel sequencing panels, exome, or genome sequencing, complemented by electromyography, muscle imaging, and biopsy when indicated and available. The workshop highlighted the need for harmonized classification across databases, patient engagement, and global representation to support precise diagnosis, genotype-phenotype correlation, and equitable access to care and research.
HYPOTHESIS SIGNIFICANT: Cochlear implant (CI) insertion trauma, as evidenced by fracture of the osseous spiral lamina (OSL), is associated with localized "dead zones" and focal spiral ganglion neuron (SGN) loss.
BACKGROUND: Hearing and structure preservation approaches to CI insertion aim to minimize trauma and preserve residual SGNs. In cases of significant insertion trauma, peripheral axons running through the bony OSL inherently become damaged if the OSL is fractured. The current investigation sought to determine if the relative location of OSL fracture was associated with focal areas of SGN loss.
METHODS: Five adult ears from the Mass Eye and Ear Otopathology Laboratory were identified with OSL fractures. When available, contralateral ears were also analyzed for comparison. Digitized e-Slides were used to create 3D cochlear reconstructions, and a coordinate system relative to the round window allowed for % distance along Rosenthal canal (RC) assignment of SGNs and OSL fracture locations. Abrupt changes in SGN density, defined as a drop >50% within a 5% segment along RC were used as criteria for a significant and focal SGN loss. Insertion trauma in the form of electrode translocation and spiral ligament (SL) perforation was also characterized.
RESULTS: OSL fracture lengths ranged from approximately 72 to 109 degrees about the modiolus, with a median fracture length of 75 degrees. Total SGN counts ranged from 16,810 to 22,260. Abrupt and focal drops of >50% in SGN density occurred in all 5 temporal bones with OSL fracture. In 3 of the cases, there were areas of localized "dead zones" at or immediately adjacent to the OSL fracture site, whereas in the remaining 2 cases, drops were seen in various areas across the cochlea. The case with the longest fracture demonstrated nearly a complete loss of neurons apical to the deepest fracture location. Ears with OSL fractures demonstrate a higher number of "dead zones" than the contralateral ears used for comparison, with median values of 3 and 2, respectively. Cases with an OSL fracture, electrode translocation, and SL perforation demonstrated a notably higher number of "dead zones" (median = 3) as compared with ears with only 1 or 2 CI insertional trauma injuries (median = 2).
CONCLUSION: In temporal bones from CI patients, OSL fractures explain some-but not all-of the abrupt SGN loss observed following traumatic CI insertions. Distinct regions of SGN density observed across the length of these cochlea indicate multifactorial processes likely contribute to relative SGN "dead zones."
Two curcumin derivatives, structurally related to the CRANAD family of compounds, were investigated for their theranostic properties in Alzheimer's disease. They exhibited fluorescence emission in the NIR region (650-690 nm) with a significant Stokes' shift (70-90 nm). Their affinity for Aβ aggregates, oligomers and monomers allows to detect, differentiate and map in vitro the various amyloid species within and around the plaques by fluorescence microscopy. Fluorescence lifetime microscopy, a robust and sensitive technique allowing to visualize biomolecules with high spatial resolution at nanomolar level, was employed to discriminate the less soluble and more toxic species from the more soluble ones by determination of fluorescence lifetime values at the core and the periphery of the β-amyloid plaques, without the need for the use of antibodies. In vivo brain images show that the fluorescence signals of the sensors are 5-6 times higher for transgenic mice with aberrant proteins than wild type mice after intraperitoneal injection, differentiating plaques of amyloid beta (Aβ) protein in real samples in vivo. These experiments also showed a good blood brain barrier penetration of the sensors, which remain in the brain for 90-120 min, opening up the possibility of their therapeutic use. In vitro studies showed a good activity of both compounds as inhibitors of Aβ aggregation into small soluble oligomers and large insoluble aggregates and also the inhibition of tau protein aggregation, both in a dose-dependent manner. These studies confirm that both compounds have an unprecedented profile that justifies their further study as small-molecule theranostic agents in AD.
Primary fetal pleural effusion involves the accumulation of fluid in the fetal pleural space, posing considerable challenges for perinatal diagnosis and management. Primary effusions, emerging from the maldevelopment of lymphatic vessels, differ significantly from secondary effusions, which are associated with a spectrum of anomalies and conditions, affecting clinical approach and prognosis. The diagnosis of primary fetal pleural effusion is one of exclusion. The natural history of the condition ranges from spontaneous resolution in mild cases to progression to life-threatening complications. Fetal interventional strategies, including thoracocentesis, pleurodesis, and thoracoamniotic shunt placement, have evolved with varying degrees of success. The prognosis is largely affected by gestational age at diagnosis, the presence of hydrops, and the implementation of fetal intervention, with improved outcomes observed in non-hydropic fetuses. This narrative review focuses on primary fetal pleural effusion, detailing its diagnosis, natural history, management options, and outcomes, with the aim of clarifying the best approaches to improve outcomes for affected fetuses.
BACKGROUND: Postmenopausal osteoporosis is a highly prevalent disease associated with substantial morbidity and mortality. The most recently introduced osteoporosis medication is romosozumab, a monoclonal antibody with a unique mechanism of action that increases bone mineral density (BMD) more than other agents by both stimulating new bone formation and inhibiting resorption. The drug's stimulation of bone formation, however, wanes after several months. The use of romosozumab is limited by cost, the inconvenience of monthly clinic-administered injections, and its cardiovascular risk profile. In this trial, we aimed to test the hypothesis that a shorter course of romosozumab might be equally effective as the standard regimen.
METHODS: We did a 12-month, prospective, open-label, randomised, controlled, non-inferiority trial of 50 postmenopausal women at high risk of fracture. The study was done at a single academic medical centre in the USA. Participants were randomly assigned to receive 3 months of romosozumab (210 mg by subcutaneous injection, monthly) followed by 9 months of denosumab (60 mg by subcutaneous injection, every 6 months; 3-month ROMO group) or 12 months of romosozumab (12-month ROMO group). The primary endpoint was the percentage change in total hip BMD. The non-inferiority threshold was set at 2%. The trial was registered at ClinicalTrials.gov, NCT05010590.
FINDINGS: Between March 2, 2022, and May 2, 2023, we screened 188 participants. Of those, 102 (54%) were ineligible and 36 (19%) declined to participate. We randomly assigned 50 participants to either the 3-month ROMO group (24 [48%] participants) or the 12-month ROMO group (26 [52%] participants). Study participants completing at least one post-baseline visit were included in the analysis (modified intention-to-treat analysis). The mean age of participants was 69·6 years (SD 4·5). The mean 12-month change in total hip BMD was 5·7% (SD 3·3) in the 3-month romosozumab group and 6·0% (3·2) in the 12-month romosozumab group, meeting the prespecified non-inferiority threshold. Adverse events (back pain, cough, fatigue, headache, joint pain, muscle cramps, muscle pain, palpitations, paraesthesia, reaction at injection site, rhinorrhoea, skin rash, and swelling) were balanced between groups.
INTERPRETATION: In postmenopausal women at high risk of fracture, 3 months of romosozumab followed by 9 months of denosumab was non-inferior to 12 months of romosozumab in increasing total hip BMD. Given the expense, injection burden, and potential adverse effects of romosozumab, this abbreviated approach could broaden access to this uniquely effective therapy.
FUNDING: US National Institute of Arthritis and Musculoskeletal and Skin Diseases and US National Center for Advancing Translational Science.
BACKGROUND: Experimental models suggest that in utero photoperiod influences circadian regulation and systems tied to later-life anxiety, depression, and addiction. Whether in utero photoperiod is associated with mental health and substance use in adolescents and young adults remains unknown.
METHODS: 10,721 full term born children from the GUTS cohort contributed to these analyses. Total photoperiod was calculated by summing daily light hours across 280 gestational days using each offspring's exact birth date and state. We used multivariable adjusted generalized estimating equations, logistic regression, and linear regression to estimate odds ratios (ORs) and mean differences (MDs) for self-reported mental health and substance use outcomes across quintiles of in utero photoperiod.
RESULTS: We observed no association between in utero photoperiod and mental health outcomes. Marijuana, opioids, stimulants, and alcohol use also did not differ by photoperiod. However, offspring in the top versus bottom photoperiod had lower odds of ever smoking [MV-ORQ5vsQ1, 0.89; 95% CI: 0.80,0.99; P = 0.08], smoked fewer cigarettes per day [MV-MDQ5vsQ1, -0,16; 95%CI: -0.29,-0.04; P = 0.02], and showed lower nicotine dependence [MV-MDQ5vsQ1, -0,46; 95%CI: -0.8,-0.12; P = 0.007]. No sex interactions were observed for mental health; for smoking and marijuana, males had lower odds of use.
CONCLUSION: In utero photoperiod was not associated with mental health. Greater prenatal light exposure was linked to reduced smoking, but not alcohol or marijuana use, in offspring. Further research should examine cumulative prenatal and postnatal photoperiod effects on these outcomes.
BACKGROUND: [18F]flurpiridaz is a newly FDA-approved tracer for positron emission tomography myocardial perfusion imaging (PET MPI) with a long half-life and improved physical characteristics. However, its long half-life leads to residual rest activity. Prior trials used 30 to 60 minutes delays between rest and stress injections and proposed stress-to-rest dose ratios of 1:2 to 1:3 to mitigate the potential impact of residual rest counts on the stress myocardial perfusion images.
OBJECTIVE: To evaluate the effect of stress-to-rest dose ratio and time interval between injections on residual activity.
METHODS: We analyzed consecutive 115 patients who underwent PET MPI with [18F]flurpiridaz. Relative residual activity was calculated as the ratio of tissue activity concentration (kBq/mL) in the first stress frame to that in the stress tissue phase. Linear regression was used to assess the association of dose ratio and injection time interval with global residual activity. The optimal dose ratio cutoff was identified. Mixed-effects models with interaction terms were used to assess whether the effect varied across vascular territories.
RESULTS: A total of 115 patients underwent PET MPI. Results showed that increasing the stress-to-rest dose ratio was significantly associated with lower relative residual activity (β = -3.41; 95% confidence interval (CI): -4.72; -2.11 per 1-unit increase), while increasing the time interval between injections up to 39 minutes showed no significant association (β = 0.03 95% CI: -0.12; 0.17 per 1-minute increase) within this time window. The optimal cutoff dose ratio to achieve relative residual activity <20% ranged between 3.2 and 4.3.
CONCLUSION: Increasing the stress-to-rest dose ratio between 3.2 and 4.3 effectively reduces residual activity to <20% of the stress dose across all time intervals, thereby enabling back-to-back imaging and improving protocol efficiency on digital PET systems. Further validation is warranted for older, non-digital scanners.