Missense mutations in the central domains of cardiac myosin binding protein-C and their potential contribution to hypertrophic cardiomyopathy.

Myosin binding protein-C (MyBP-C) is a multidomain protein that regulates muscle contraction. Mutations in MYBPC3, the gene encoding for the cardiac variant (henceforth called cMyBP-C), are amongst the most frequent causes of hypertrophic cardiomyopathy. Most mutations lead to a truncated version of cMyBP-C, which is most likely unstable. However, missense mutations have also been reported, which tend to cluster in the central domains of the cMyBP-C molecule. This suggests that these central domains are more than just a passive spacer between the better characterized N- and C-terminal domains. Here, we investigated the potential impact of four different missense mutations, E542Q, G596R, N755K, and R820Q, which are spread over the domains C3 to C6, on the function of MyBP-C on both the isolated protein level and in cardiomyocytes in vitro. Effect on domain stability, interaction with thin filaments, binding to myosin, and subcellular localization behavior were assessed. Our studies show that these missense mutations result in slightly different phenotypes at the molecular level, which are mutation specific. The expected functional readout of each mutation provides a valid explanation for why cMyBP-C fails to work as a brake in the regulation of muscle contraction, which eventually results in a hypertrophic cardiomyopathy phenotype. We conclude that missense mutations in cMyBP-C must be evaluated in context of their domain localization, their effect on interaction with thin filaments and myosin, and their effect on protein stability to explain how they lead to disease.

Association of hospital-level factors with utilization of sentinel lymph node biopsy in patients with early-stage vulvar cancer.

OBJECTIVE: To evaluate utilization of sentinel lymph node biopsy (SLNB) for early-stage vulvar cancer at minority-serving hospitals and low-volume facilities. METHODS: Between 2012-2018, individuals with T1b vulvar squamous cell carcinoma were identified using the National Cancer Database. Patient, facility, and disease characteristics were compared between patients undergoing SLNB or inguinofemoral lymph node dissection (IFLD). Multivariable logistic regression, adjusted for patient, facility, and disease characteristics, was used to evaluate factors associated with SLNB. Kaplan-Meier survival analysis using log rank test and Cox regression was performed. RESULTS: Of the 3,532 patients, 2,406 (68.1%) underwent lymph node evaluation, with 1,704 (48.2%) undergoing IFLD and 702 (19.8%) SLNB. In a multivariable analysis, treatment at minority-serving hospitals (OR 0.39, 95% CI 0.19-0.78) and low-volume hospitals (OR 0.44, 95% CI 0.28-0.70) were associated with significantly lower odds of undergoing SLNB compared to receiving care at non-minority-serving and high-volume hospitals, respectively. While SLNB utilization increased over time for the entire cohort and stratified subgroups, use of the procedure did not increase at minority-serving hospitals. After controlling for patient and tumor characteristics, SLNB was not associated with worse OS compared to IFLD in patients with positive (HR 1.02, 95% CI 0.63-1.66) or negative (HR 0.92, 95% CI 0.70-1.21) nodal pathology. CONCLUSIONS: For patients with early-stage vulvar cancer, treatment at minority-serving or low-volume hospitals was associated with significantly decreased odds of undergoing SLNB. Future efforts should be concentrated toward ensuring that all patients have access to advanced surgical techniques regardless of where they receive their care.

Trends in the use of neoadjuvant chemotherapy for low-grade serous ovarian cancer in the United States.

OBJECTIVE: To describe trends in neoadjuvant chemotherapy (NACT) use for low-grade serous ovarian carcinoma (LGSOC) and to quantify associations between NACT and extent of cytoreductive surgery. METHODS: We identified women treated for stage III or IV serous ovarian cancer in a Commission on Cancer accredited program between January 2004-December 2020. Regression models were developed to evaluate trends in NACT use for LGSOC, to identify factors associated with receipt of NACT, and to quantify associations between NACT and bowel or urinary resection at the time of surgery. Demographic and clinical factors were used for confounder control. RESULTS: We observed 3350 patients who received treatment for LGSOC during the study period. The proportion of patients who received NACT increased from 9.5% in 2004 to 25.9% in 2020, corresponding to an annual percent change of 7.2% (95% CI 5.6-8.9). Increasing age (rate ratio (RR) 1.15; 95% CI 1.07-1.24), and stage IV disease (RR 2.66; 95% CI 2.31-3.07) were associated with a higher likelihood of receiving NACT. For patients with high-grade disease, NACT was associated with a decrease in likelihood of bowel or urinary surgery (35.3% versus 23.9%; RR 0.68, 95% CI 0.65-0.71). For LGSOC, NACT was associated with a higher likelihood of these procedures (26.6% versus 32.2%; RR 1.24, 95% CI 1.08-1.42). CONCLUSION: NACT use among patients with LGSOC has increased from 2004 to 2020. While NACT was associated with a lower rate of gastrointestinal and urinary surgery among patients with high-grade disease, patients with LGSOC receiving NACT were more likely to undergo these procedures.

Association between obesity and cervical intraepithelial neoplasia: results from a case control study in south western Uganda.

BACKGROUND: Though obesity has been said to be associated with a number of malignancies including cervical cancer, its association with cervical intraepithelial neoplasia (CIN) is still a contentious issue. This study was designed to determining the prevalence and association between obesity and CIN. METHODS: This was an unmatched case control study, involving women with cervical intraepithelial neoplasia (cases) and those negative for intraepithelial lesions or malignancy (controls) at the cervical cancer clinic of Mbarara Regional Referral Hospital, in south-western Uganda, between April and November 2022. Cases and controls provided written informed consent and were recruited in a ratio of 1:1. Cases were identified by visual inspection with acetic acid (VIA) and subsequent confirmation with cytology and/or histology. Demographic information was collected using an enrolment form and height, weight and waist circumference were recorded. We calculated body mass index (BMI) and identified obese women as those with body mass index of ≥ 30 kg/m2 from both case and control groups. Central obesity was defined as waist: height ration of ≥ 0.5. Data was analysed using STATA version 17. Categorical variables were analysed using proportions, chi-square and logistic regression analysis to determine association between obesity and CIN. Our level of statistical significance was set at ≤ 0.05. RESULTS: The prevalence of general and central obesity among cases was 25.5% (24/94) and 0% (0/94) respectively while the prevalence of general and central obesity among controls was 33.3% (37/111) and 0% (0/111) respectively. There was an increased prevalence of general obesity among women with low grade squamous intraepithelial lesions (LSIL). However, there was no statistically significant association between general obesity and CIN. Factors associated with general obesity included residing in Mbarara city (AOR 2.156, 95%CI 1.085-4.282, P-value 0.028), age group of 31-45 years (AOR 2.421, 95%CI 1.577-9.705, P-value 0.003) and ≥ 46 years (AOR 1.971, 95%CI 1.022-11.157, P-value 0.046). CONCLUSION: We observed an increased prevalence of general obesity among women with LSIL. However, there was no association between obesity and CIN. Factors associated with general obesity included residing in Mbarara city, and being in the age groups of 31-40 and ≥ 46 years. This highlights the need to rethink management of CIN to control other non-communicable diseases that could arise due to general obesity.

Reliability and Validity of a Method for the Assessment of Sport Rock Climbers' Isometric Finger Strength.

ABSTRACT: Torr, O, Randall, T, Knowles, R, Giles, D, and Atkins, S. The reliability and validity of a method for the assessment of sport rock climbers' isometric finger strength. J Strength Cond Res 36(8): 2277-2282, 2022-Isometric strength of the finger flexors is considered to be one of the main physical determinants of sport rock climbing performance. We set out to determine the test-retest reliability and criterion validity of a low resource maximal isometric finger strength (MIFS) testing protocol that uses a pulley system to add or remove weight to/from a climber's body. To determine test-retest reliability, 15 subjects' MIFS was assessed on 2 occasions, separated by a minimum of 48 hours. Body mass and maximum load were recorded on both occasions. Intra-class correlation coefficients (ICCs) between visits for all variables were very good (ICC > 0.91), with small bias and effect sizes-particularly when expressed as a percentage of body mass (ICC = 0.98, 95% confidence interval 0.93-0.99). To determine the criterion validity of MIFS and climbing ability, data of 229 intermediate to higher elite climbers were compared. Pearson's product moment correlations demonstrated good agreement, again particularly between total load when expressed as a percentage of body mass and climbing performance ( r = 0.421-0.503). The results illustrate the sensitivity of a simple test for the determination of MIFS in intermediate to height elite climbers from an ecologically valid, climbing specific test that only requires equipment found at most climbing walls. This low resource test protocol for the assessment of isometric finger strength has wide-reaching utility, for instance when assessing strength before and after a training intervention or when prescribing load intensities for exercises aimed at improving maximal finger strength.

A small-molecule activator of kinesin-1 drives remodeling of the microtubule network.

The microtubule motor kinesin-1 interacts via its cargo-binding domain with both microtubules and organelles, and hence plays an important role in controlling organelle transport and microtubule dynamics. In the absence of cargo, kinesin-1 is found in an autoinhibited conformation. The molecular basis of how cargo engagement affects the balance between kinesin-1's active and inactive conformations and roles in microtubule dynamics and organelle transport is not well understood. Here we describe the discovery of kinesore, a small molecule that in vitro inhibits kinesin-1 interactions with short linear peptide motifs found in organelle-specific cargo adaptors, yet activates kinesin-1's function of controlling microtubule dynamics in cells, demonstrating that these functions are mechanistically coupled. We establish a proof-of-concept that a microtubule motor-cargo interface and associated autoregulatory mechanism can be manipulated using a small molecule, and define a target for the modulation of microtubule dynamics.

SKIP controls lysosome positioning using a composite kinesin-1 heavy and light chain-binding domain.

The molecular interplay between cargo recognition and regulation of the activity of the kinesin-1 microtubule motor is not well understood. Using the lysosome adaptor SKIP (also known as PLEKHM2) as model cargo, we show that the kinesin heavy chains (KHCs), in addition to the kinesin light chains (KLCs), can recognize tryptophan-acidic-binding determinants on the cargo when presented in the context of an extended KHC-interacting domain. Mutational separation of KHC and KLC binding shows that both interactions are important for SKIP-kinesin-1 interaction in vitro and that KHC binding is important for lysosome transport in vivo However, in the absence of KLCs, SKIP can only bind to KHC when autoinhibition is relieved, suggesting that the KLCs gate access to the KHCs. We propose a model whereby tryptophan-acidic cargo is first recognized by KLCs, resulting in destabilization of KHC autoinhibition. This primary event then makes accessible a second SKIP-binding site on the KHC C-terminal tail that is adjacent to the autoinhibitory IAK region. Thus, cargo recognition and concurrent activation of kinesin-1 proceed in hierarchical stepwise fashion driven by a dynamic network of inter- and intra-molecular interactions.

Worthy of further consideration: An updated meta-analysis to address the feasibility, acceptability, safety and efficacy of thermal ablation in the treatment of cervical cancer precursor lesions.

Treatment of preinvasive lesions is critical to the success of secondary prevention of cervical cancer. In many settings, however, excision or ablation of preinvasive lesions can prove challenging. Thermal ablation (TA) is a form of treatment for cervical precancer that may present fewer logistical challenges in resource limited settings. In 2013, Dolman and colleagues wrote a meta-analysis of publications reporting cure rates from TA. This included only one article from a low or middle-income country (LMIC). We updated Dolman's meta-analysis to include more recent articles from LMICs. A formal review of the world literature was performed for the years 2014-2017. Article titles and abstracts were reviewed for relevance; full articles were assessed for quality. The primary endpoint was treatment outcome for cervical intraepithelial neoplasia grade 2 or higher (CIN2+). The I2 statistic was used to assess heterogeneity between studies. Studies were stratified by geographic region, decade that the study was published, World Bank economic classification of the country where the study was performed, and other factors. We reviewed 34 total reports and included 23 in our meta-analysis, including 10,995 and 6371 patients, respectively. A total of 7 studies were performed in LMICs, including 6 studies included in the meta-analysis. The overall response rate for TA treatment of biopsy proven CIN2+ was 93.8%. Consistent with the wide variety of settings and patient populations, there was significant heterogeneity between studies. TA appears to be an effective treatment for CIN2+ across a variety of settings, including in LMICs.

Proceedings From the 1st International Conference 'Current Concepts and Controversies in Gynecologic and Urologic Oncology'.

The N.N. Alexandrov National Cancer Center of Belarus organized a collaborative international conference entitled 'Current Concepts and Controversies in Gynecologic and Urologic Oncology' with the International Gynecologic Cancer Society and the United States National Cancer Institute. International, regional, and national experts presented recent developments and local conditions in the treatment of gynecologic cancers. Findings were reviewed with the intent of optimizing the management of women with gynecologic cancers across the Commonwealth of Independent States region. At the end of the conference, a resolution was adopted to identify areas for improvement and future collaborations.

Telomerase lost?

Telomerase and telomerase-generated telomeric DNA sequences are widespread throughout eukaryotes, yet they are not universal. Neither telomerase nor the simple DNA repeats associated with telomerase have been found in some plant and animal species. Telomerase was likely lost from Diptera before the divergence of Diptera and Siphonaptera, some 260 million years ago. Even so, Diptera is one of the most successful animal orders, making up 11% of known animal species. In addition, many species of Coleoptera and Hemiptera seem to lack canonical telomeric repeats at their chromosome ends. These and other insects that appear to lack canonical terminal repeat sequences account for another 10-15% of animal species. Conversely, the silk moth Bombyx mori maintains canonical telomeric sequences at its chromosome ends but seems to lack a functional telomerase. We speculate that a telomere-specific capping complex that recognizes the telomeric repeats and protects chromosome ends is the determining factor in maintaining canonical telomeric sequences and that telomerase is an early and efficacious mechanism for satisfying the needs of capping complex. There are alternate mechanisms for maintaining chromosome ends that do not depend on telomerase, such as recombination found in some human cancer cells and yeast mutants. These mechanisms may maintain the canonical telomeric repeats or allow the terminal sequence to evolve when specificity of the capping complex for terminal repeat sequences is weak.

New Insights into Cockroach Allergens.

PURPOSE OF REVIEW: This review addresses the most recent developments on cockroach allergen research in relation to allergic diseases, especially asthma. RECENT FINDINGS: The number of allergens relevant to cockroach allergy has recently expanded considerably up to 12 groups. New X-ray crystal structures of allergens from groups 1, 2, and 5 revealed interesting features with implications for allergen standardization, sensitization, diagnosis, and therapy. Cockroach allergy is strongly associated with asthma particularly among children and young adults living in inner-city environments, posing challenges for disease control. Environmental interventions targeted at reducing cockroach allergen exposure have provided conflicting results. Immunotherapy may be a way to modify the natural history of cockroach allergy and decrease symptoms and asthma severity among sensitized and exposed individuals. The new information on cockroach allergens is important for the assessment of allergen markers of exposure and disease, and for the design of immunotherapy trials.

Proteases of Dermatophagoides pteronyssinus.

Since the discovery that Der p 1 is a cysteine protease, the role of proteolytic activity in allergic sensitization has been explored. There are many allergens with proteolytic activity; however, exposure from dust mites is not limited to allergens. In this paper, genomic, transcriptomic and proteomic data on Dermatophagoides pteronyssinus (DP) was mined for information regarding the complete degradome of this house dust mite. D. pteronyssinus has more proteases than the closely related Acari, Dermatophagoides farinae (DF) and Sarcoptes scabiei (SS). The group of proteases in D. pteronyssinus is found to be more highly transcribed than the norm for this species. The distribution of protease types is dominated by the cysteine proteases like Der p 1 that account for about half of protease transcription by abundance, and Der p 1 in particular accounts for 22% of the total protease transcripts. In an analysis of protease stability, the group of allergens (Der p 1, Der p 3, Der p 6, and Der p 9) is found to be more stable than the mean. It is also statistically demonstrated that the protease allergens are simultaneously more highly expressed and more stable than the group of D. pteronyssinus proteases being examined, consistent with common assumptions about allergens in general. There are several significant non-allergen outliers from the normal group of proteases with high expression and high stability that should be examined for IgE binding. This paper compiles the first holistic picture of the D. pteronyssinus degradome to which humans may be exposed.

[Costs associated with multiresistant bacteria in neurorehabilitation]. / Mehrkosten durch multiresistente Erreger in der Neurorehabilitation.

BACKGROUND AND OBJECTIVES: The number of patients with multiresistant bacteria (MRB) in rehabilitation facilities is increasing. The increasing costs of hygienic isolation measures reduce resources available for core rehabilitation services. In addition to the existing lack of care, patients with MRB are at further risk of being given lower priority for admission to rehabilitation facilities. Therefore, the Hygiene Commission of the German Society for Neurorehabilitation (DGNR) attempted to quantify the overall risk for deterioration of rehabilitation care due to the financial burden of MRB. MATERIALS AND METHODS: To analyze the added costs associated with the rehabilitation of patients with MBR, the DGNR Hygiene Commission identified criteria for a cost assessment. Direct (consumables, personnel and miscellaneous costs) and indirect costs of loss of opportunity were evaluated in seven neurorehabilitation centers in different states across Germany. RESULTS: On average, hygienic isolation measures amounted to direct costs of 144 € per day (47 € consumables, 92 € personnel, 5 € for other costs such as extra transportation expenditure) and indirect costs of 274 €, totaling 418 € per patient with MRB per day. Given that approximately 10% of patients had MRB, the added costs of hygienic isolation measures equaled about one tenth of the overall budget of a rehabilitation center and can be expected to rise with the increasing numbers of patients with MRB. CONCLUSIONS: Admission of patients carrying MRB to neurorehabilitation centers triggers added costs that critically diminish the overall capacity for centers to provide their core rehabilitation services.

Emergence and evolution of Zfp36l3.

In most mammals, the Zfp36 gene family consists of three conserved members, with a fourth member, Zfp36l3, present only in rodents. The ZFP36 proteins regulate post-transcriptional gene expression at the level of mRNA stability in organisms from humans to yeasts, and appear to be expressed in all major groups of eukaryotes. In Mus musculus, Zfp36l3 expression is limited to the placenta and yolk sac, and is important for overall fecundity. We sequenced the Zfp36l3 gene from more than 20 representative species, from members of the Muridae, Cricetidae and Nesomyidae families. Zfp36l3 was not present in Dipodidae, or any families that branched earlier, indicating that this gene is exclusive to the Muroidea superfamily. We provide evidence that Zfp36l3 arose by retrotransposition of an mRNA encoded by a related gene, Zfp36l2 into an ancestral rodent X chromosome. Zfp36l3 has evolved rapidly since its origin, and numerous modifications have developed, including variations in start codon utilization, de novo intron formation by mechanisms including a nested retrotransposition, and the insertion of distinct repetitive regions. One of these repeat regions, a long alanine rich-sequence, is responsible for the full-time cytoplasmic localization of Mus musculus ZFP36L3. In contrast, this repeat sequence is lacking in Peromyscus maniculatus ZFP36L3, and this protein contains a novel nuclear export sequence that controls shuttling between the nucleus and cytosol. Zfp36l3 is an example of a recently acquired, rapidly evolving gene, and its various orthologues illustrate several different mechanisms by which new genes emerge and evolve.

Cancer and the world's poor: What's a gynecologic cancer specialist to do?

Women in low- and middle-income countries (LMICs) face a drastically increased burden of cervical cancer and the same burden of other gynecologic cancers as do women in high-income countries, yet there are few resources or specialists to meet their needs. 85% of deaths from cervical cancer occur in LMICs. As the population of these regions age, and as death from infectious diseases decrease, this burden will increase further without strong intervention. There are few cancer specialists in LMICs and training in gynecologic cancer care is rare. Gynecologic cancer specialists are uniquely positioned to meet this challenge as advocates, educators and experts. On behalf of the SGO International Committee, we call on our colleagues to meet this historic challenge.

Health Care Disparities in Hereditary Ovarian Cancer: Are We Reaching the Underserved Population?

OPINION STATEMENT: Ovarian cancer is an uncommon but deadly disease. There is no effective screening for the disease, and the majority of women with ovarian cancer present in advanced stage and eventually die from their disease. The majority of families with multiple cases of breast and ovarian cancer are found to carry germline mutations in BRCA1/2. Recent, more sensitive sequencing techniques have shown that nearly 20 % of ovarian cancer is associated with germline mutations in cancer susceptibility genes, with approximately 15 % accounted for by deleterious mutations in BRCA1/2. Women found to have mutations in BRCA1/2 can be empowered to make decisions on reproduction, cancer prevention, or treatment that may either avoid cancer or prolong survival. Though initial studies suggested that African American (AA) women were significantly less likely than White women to have mutations in BRCA1/2, this has been found to be untrue. Despite this revelation, and the clear importance of BRCA1/2 mutation status to appropriate clinical management, AA women still undergo genetic counseling and testing at much lower rates than do comparable White women. This disparity is not explained by factors such as calculated risk of a mutation, insurance coverage, or previous knowledge of the availability of testing. To date, no effective strategies have been identified that can overcome this disparity. Possible approaches include use of patient navigators, online social media, or EMR-based decision support aids. Funders should support research in this area, as it represents an actionable means to decrease the burden of ovarian and breast cancer in AA women.

Sister Society Meeting on Global Education Development and Collaboration: Meeting Report.

OBJECTIVES: To identify common barriers to teaching and training and to identify strategies that would be useful in developing future training programs in gynecologic oncology in low- and middle- income countries. METHODS: There is a lack of overall strategy to meet the needs of education and training in gynecologic oncology in low- and middle- income countries, the leaderships of sister societies and global health volunteers met at the European Society of Gynecologic Oncology in October 23, 2015. The challenges of the training programs supported by gynecologic oncology societies, major universities and individual efforts were presented and discussed. Strategies to improve education and training were identified. RESULTS: Major challenges include language barriers, limited surgical equipment, inadequate internet access, lack of local support for sustainability in training programs, inadequate pathology and radiation oncology, finance and a global deficiency in identifying sites and personnel in partnering or developing training programs. The leaderships identified various key components including consultation with the local Ministry of Health, local educational institutions; inclusion of the program into existing local programs, a needs assessment, and the development of curriculum and regional centers of excellence. CONCLUSIONS: Proper preparation of training sites and trainers, the development of global curriculum, the establishment of centers of excellence, and the ability to measure outcomes are important to improve education and training in gynecologic oncology in low- and middle- income countries.