Mechanisms of APOBEC3 mutagenesis in human cancer cells.

The APOBEC3 family of cytosine deaminases has been implicated in some of the most prevalent mutational signatures in cancer1-3. However, a causal link between endogenous APOBEC3 enzymes and mutational signatures in human cancer genomes has not been established, leaving the mechanisms of APOBEC3 mutagenesis poorly understood. Here, to investigate the mechanisms of APOBEC3 mutagenesis, we deleted implicated genes from human cancer cell lines that naturally generate APOBEC3-associated mutational signatures over time4. Analysis of non-clustered and clustered signatures across whole-genome sequences from 251 breast, bladder and lymphoma cancer cell line clones revealed that APOBEC3A deletion diminished APOBEC3-associated mutational signatures. Deletion of both APOBEC3A and APOBEC3B further decreased APOBEC3 mutation burdens, without eliminating them. Deletion of APOBEC3B increased APOBEC3A protein levels, activity and APOBEC3A-mediated mutagenesis in some cell lines. The uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas the loss of the translesion polymerase REV1 decreased overall mutation burdens. Together, these data represent direct evidence that endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells. Our results identify APOBEC3A as the main driver of these mutations, indicate that APOBEC3B can restrain APOBEC3A-dependent mutagenesis while contributing its own smaller mutation burdens and dissect mechanisms that translate APOBEC3 activities into distinct mutational signatures.

A comprehensive patient-specific prediction model for temporomandibular joint osteoarthritis progression.

Temporomandibular joint osteoarthritis (TMJ OA) is a prevalent degenerative disease characterized by chronic pain and impaired jaw function. The complexity of TMJ OA has hindered the development of prognostic tools, posing a significant challenge in timely, patient-specific management. Addressing this gap, our research employs a comprehensive, multidimensional approach to advance TMJ OA prognostication. We conducted a prospective study with 106 subjects, 74 of whom were followed up after 2 to 3 y of conservative treatment. Central to our methodology is the development of an innovative, open-source predictive modeling framework, the Ensemble via Hierarchical Predictions through Nested cross-validation tool (EHPN). This framework synergistically integrates 18 feature selection, statistical, and machine learning methods to yield an accuracy of 0.87, with an area under the ROC curve of 0.72 and an F1 score of 0.82. Our study, beyond technical advancements, emphasizes the global impact of TMJ OA, recognizing its unique demographic occurrence. We highlight key factors influencing TMJ OA progression. Using SHAP analysis, we identified personalized prognostic predictors: lower values of headache, lower back pain, restless sleep, condyle high gray level-GL-run emphasis, articular fossa GL nonuniformity, and long-run low GL emphasis; and higher values of superior joint space, mouth opening, saliva Vascular-endothelium-growth-factor, Matrix-metalloproteinase-7, serum Epithelial-neutrophil-activating-peptide, and age indicate recovery likelihood. Our multidimensional and multimodal EHPN tool enhances clinicians' decision-making, offering a transformative translational infrastructure. The EHPN model stands as a significant contribution to precision medicine, offering a paradigm shift in the management of temporomandibular disorders and potentially influencing broader applications in personalized healthcare.

Vicarious excretion of 99mTc-pyrophosphate in the gallbladder.

Vicarious excretion of tracer and contrast media is a known phenomenon and is not fully understood [1,2]. We report a case of unexpected vicarious excretion of 99mTc-pyrophosphate in the gallbladder seen on a scan performed to evaluate suspected cardiac amyloidosis, which is the first report of this phenomenon to the best of our knowledge.

Relationship between academic procrastination and self-efficacy amongst dental undergraduate students at a public university in Karachi, Pakistan.

Objective: To compare the procrastination and self-efficacy scores among students with respect to the academic year of dental undergraduate programme, and to assess the relationship between self-efficacy and academic procrastination among the students. METHODS: The descriptive study was conducted at Sindh Institute of Oral Health Sciences, Jinnah Sindh Medical University, Karachi, from January to March 2023, and comprised medical students of either gender from all the 4 academic years. Data was collected using a structured questionnaire whose validity was assessed using a pilot study. Data was analysed using SPSS 18. RESULTS: Of the 136 students, 84(61.8%) were females and 52(38.2%) were males. There were 34(25%) students from the 1st year, 32(23.5%) from 2nd year, 38(28%) from the 3rd year, and 32(23.5%) from the final year. The highest mean score for procrastination was from 3rd year students 67.7±12.8, while the highest mean score for self-efficacy was from 1st year students 30.2±4. There was no significant difference in terms of gender (p>0.05). Procrastination scores had a significant association with the academic year (p=0.016). Conclusion: Procrastination scores were high among the dental students with the highest score from 3rd year students. The academic environment should provide support help the students devise strategies to optimally utilise the available time.

Standard Adult Gastric Emptying Scintigraphy Criteria Is Applicable for Partial Meal Ingestion.

BACKGROUND/AIMS: Gastric emptying scintigraphy is commonly performed to assess for dysmotility. A standardized meal with associated threshold criteria was established in 2000 to enable robust interpretation. However, no guidance is available to interpret results when patients do not ingest the entire meal. The purpose of this study is to determine the continued appropriateness of the threshold criteria in contemporary clinical practice and its relevance for partially ingested meals. METHODS: This retrospective study analyzed patients (n = 1365 total) who underwent solid-phase gastric emptying scintigraphy at an academic medical center. Patients were stratified based on their completion of the standard meal. Patients were further stratified into normal and delayed gastric emptying cohorts based on the current criteria. Percent gastric retention values at 1, 2, 3, and 4 h were compared. RESULTS: Median (95% upper reference) normal gastric retention values for the complete standard meal were 64% (87%) at 1 h, 25% (60%) at 2 h, 13% (54%) at 3 h and 4% (9%) at 4 h. Consumption of at least 50% of the standard meal yielded similar retention; 53% (86%) at 1 h, 19% (58%) at 2 h, 6% (29%) at 3 h and 3% (10%) at 4 h. There was no significant age- or gender-specific differences using the current criteria, and no differences were observed based on diabetic status. Retention values matched well with the current criteria and validated with data-driven clustering. CONCLUSION: Adult normative standards for gastric emptying scintigraphy are appropriate for differentiating normal and delayed populations and can be applied to partial meals with at least 50% completion.

Evaluation Of Development Of Clinical Reasoning Skills In Dental Students Through Diagnostic Thinking Inventory.

Objective: To assessthe clinical reasoning skills among dentalstudents, and to compare the diagnostic thinking ability of male and female students. METHODS: The cross-sectionalstudy was conducted from May to July 2021 at a public-sector dental school in Karachi, and comprised students of both genders from across allthe four years ofdentalschool.Datawas collectedusing thediagnostic thinking inventory which also assessed flexibility in thinking and knowledge structure inmemory.Datawas analysedusing SPSS 18. RESULTS: Of the 111 forms distributed, 108(98.2%) were received duly filled; 32 (29.35%) from male students and 76(69.72) from female students. Participants from the first year were 24(22%), second year 23(21%), third year 33 (30.27%) and the fourth year 29(26.6%).The reliability of diagnostic thinking inventory was 0.906, for knowledge structure in memory 0.661, andflexibility inthinking0.573.The correlationwassignificantforstudentsintheir 2nd, 3rdand4thyearsofstudies(p=0.01) The overall mean score was <150 which was poor. Both the knowledge structure in memory, and flexibility in thinking scores were higher for females compared to males(Significant at the level of 0.01). Conclusion: The clinical reasoning skills of students were low, and the diagnostic thinking ability of female students was better than that of their male counterparts.

Association between maternal chronic apical periodontitis (CAP) and low birth weight preterm birth (LBWPT).

OBJECTIVE: To determine the association between maternal chronic apical periodontitis and low birth weight preterm birth. METHODS: The case-control study was conducted at the Gynaecology Ward of the Civil Hospital, Karachi, from September 2017 to April 2018, and comprised women aged 19-48 years with singleton pregnancy delivering spontaneously. The subjects were examined for the presence of periodontitis. The mothers who delivered low birth weight preterm babies were the cases in group A and those who delivered normal birth weight babies were the controls in group B. On the delivery day, after the subject having been moved to the room, data was collected through a questionnaire to record demographic details, history of pregnancy and information about the newborn. The radiographs were assessed for the presence of chronic apical periodontitis. The association between maternal chronic apical periodontitis and low birth weight preterm birth was subsequently determined. Data was analysed using SPSS 24. RESULTS: Of the 200 subjects, 100(50%) were in group A with a mean age of 27.17±5.11 years, and 100(50%) were in group B with a mean age of 27.08±4.90 years. Low birth weight preterm birth was associated with education level and family size (p<0.05). There was no association between maternal chronic apical periodontitis and low birth weight preterm birth (p>0.05). CONCLUSIONS: There was no association between maternal chronic apical periodontitis and low birth weight preterm birth.

Trends in County-Level COVID-19 Incidence in Counties With and Without a Mask Mandate - Kansas, June 1-August 23, 2020.

Wearing masks is a CDC-recommended* approach to reduce the spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), by reducing the spread of respiratory droplets into the air when a person coughs, sneezes, or talks and by reducing the inhalation of these droplets by the wearer. On July 2, 2020, the governor of Kansas issued an executive order† (state mandate), effective July 3, requiring masks or other face coverings in public spaces. CDC and the Kansas Department of Health and Environment analyzed trends in county-level COVID-19 incidence before (June 1-July 2) and after (July 3-August 23) the governor's executive order among counties that ultimately had a mask mandate in place and those that did not. As of August 11, 24 of Kansas's 105 counties did not opt out of the state mandate§ or adopted their own mask mandate shortly before or after the state mandate was issued; 81 counties opted out of the state mandate, as permitted by state law, and did not adopt their own mask mandate. After the governor's executive order, COVID-19 incidence (calculated as the 7-day rolling average number of new daily cases per 100,000 population) decreased (mean decrease of 0.08 cases per 100,000 per day; net decrease of 6%) among counties with a mask mandate (mandated counties) but continued to increase (mean increase of 0.11 cases per 100,000 per day; net increase of 100%) among counties without a mask mandate (nonmandated counties). The decrease in cases among mandated counties and the continued increase in cases in nonmandated counties adds to the evidence supporting the importance of wearing masks and implementing policies requiring their use to mitigate the spread of SARS-CoV-2 (1-6). Community-level mitigation strategies emphasizing wearing masks, maintaining physical distance, staying at home when ill, and enhancing hygiene practices can help reduce transmission of SARS-CoV-2.

Functional imaging in primary tumour-induced osteomalacia: relative performance of FDG PET/CT vs somatostatin receptor-based functional scans: a series of nine patients.

CONTEXT: Localization of phosphatonin-producing mesenchymal tumours in patients with primary tumour-induced osteomalacia (pTIO) is challenging. Functional imaging plays an important role in the localization of these tumours. OBJECTIVE: We studied the relative performance of different functional imaging modalities ((18) F-FDG PET/CT, (99) Tc-HYNIC-TOC SPECT/CT and (68) Ga-DOTATATE PET/CT) in tumour localization in cases of pTIO. DESIGN AND METHODS: Retrospective chart evaluation of 16 patients with confirmed TIO treated from 2006 to 2013 was conducted in a tertiary care referral centre. RESULTS: Of 16, nine patients had pTIO. In these nine, the positivity rates of different functional imaging modalities were 50% for (18) F-FDG PET/CT (four of eight patients), 100% for (99) Tc-HYNIC-TOC SPECT/CT (six of six patients) and 100% for (68) Ga-DOTATATE PET/CT (seven of seven patients). Of nine patients, six were subjected to both the (99) Tc-HYNIC-TOC SPECT/CT and (68) Ga-DOTATATE PET/CT and all of them showed coregistration on the two scans. CONCLUSIONS: In patients with pTIO, the somatostatin receptor-based functional scans performed better than (18) F-FDG PET/CT in tumour localization. Amongst the somatostatin receptor-based scans, (99) Tc-HYNIC-TOC SPECT/CT and (68) Ga-DOTATATE PET/CT performed equally well for localization of tumours.

Widespread Reactive Lymphatic and Splenic FDG Avidity After mRNA COVID Vaccination.

ABSTRACT: A 75-year-old woman with history of metastatic lung adenocarcinoma in remission develops new widespread FDG-avid lymphadenopathy in the neck, chest, abdomen, and pelvis on surveillance PET/CT, as well as intense FDG uptake in the spleen, without evidence of local recurrence. Short-term follow-up PET demonstrates near-complete resolution of FDG-avid lymphatic and splenic FDG avidity without interval change in management. Further history reveals that the patient received her fifth dose of COVID mRNA vaccine 6 days before the abnormal PET. Although unilateral axillary adenopathy after COVID vaccination is well-recognized, this widespread symmetric lymphatic and splenic FDG avidity is a significantly rarer phenomenon.

Alpha-emitter Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) has become mainstream therapy of metastatic neuroendocrine tumors not controlled by somatostatin analog therapy. Currently, beta particle-emitting radiopharmaceuticals are the mainstay of PRRT. Alpha particle-emitting radiopharmaceuticals have a theoretic advantage over beta emitters in terms of improved therapeutic efficacy due to higher cancer cell death and lower nontarget tissue radiation-induced adverse events due to shorter path length of alpha particles. We discuss the available evidence for and the role of alpha particle PRRT.

Renal Collision Tumor: A Case of Small Cell Lung Cancer Metastasis to Renal Angiomyolipoma.

ABSTRACT: A 68-year-old woman presented with chest pain and shortness of breath. Imaging revealed a left hilar mass biopsy-proven as small cell cancer. Concurrently, a macroscopic fat-containing renal lesion consistent with an angiomyolipoma was observed. Systemic therapy achieved stability in the lungs and bones, and palliative radiation targeted the left hilum. However, progressive lung disease and brain metastases necessitated stereotactic radiosurgery for brain lesions. Notably, the renal angiomyolipoma exhibited increased soft tissue component and new focal uptake on FDG PET/CT. Biopsy confirmed metastatic small cell lung cancer within the renal lesion. This case highlights a rare occurrence of a renal collision tumor involving small cell cancer and angiomyolipoma.

Deep learning to estimate gestational age from fly-to cineloop videos: A novel approach to ultrasound quality control.

OBJECTIVE: Low-cost devices have made obstetric sonography possible in settings where it was previously unfeasible, but ensuring quality and consistency at scale remains a challenge. In the present study, we sought to create a tool to reduce substandard fetal biometry measurement while minimizing care disruption. METHODS: We developed a deep learning artificial intelligence (AI) model to estimate gestational age (GA) in the second and third trimester from fly-to cineloops-brief videos acquired during routine ultrasound biometry-and evaluated its performance in comparison to expert sonographer measurement. We then introduced random error into fetal biometry measurements and analyzed the ability of the AI model to flag grossly inaccurate measurements such as those that might be obtained by a novice. RESULTS: The mean absolute error (MAE) of our model (±standard error) was 3.87 ± 0.07 days, compared to 4.80 ± 0.10 days for expert biometry (difference -0.92 days; 95% CI: -1.10 to -0.76). Based on simulated novice biometry with average absolute error of 7.5%, our model reliably detected cases where novice biometry differed from expert biometry by 10 days or more, with an area under the receiver operating characteristics curve of 0.93 (95% CI: 0.92, 0.95), sensitivity of 81.0% (95% CI: 77.9, 83.8), and specificity of 89.9% (95% CI: 88.1, 91.5). These results held across a range of sensitivity analyses, including where the model was provided suboptimal truncated fly-to cineloops. CONCLUSIONS: Our AI model estimated GA more accurately than expert biometry. Because fly-to cineloop videos can be obtained without any change to sonographer workflow, the model represents a no-cost guardrail that could be incorporated into both low-cost and commercial ultrasound devices to prevent reporting of most gross GA estimation errors.

Hepatic Small Vessel Neoplasm Mimics Prostate Cancer on 18 F-DCFPyl PET/CT.

ABSTRACT: 18 F-DCFPyl is a Food and Drug Administration-approved radiotracer that targets prostate-specific membrane antigen and is used in the detection of recurrent or metastatic prostate cancer. As its use has increased, a growing number of nonprostatic disease entities have been identified that express prostate-specific membrane antigen and can mimic prostate cancer. Thus, the interpreting physician must also consider other variables such as serum prostate-specific antigen levels and the distribution of uptake to avoid an inappropriate diagnosis of metastatic prostate cancer. We describe 18 F-DCFPyl uptake associated with a hepatic small vessel neoplasm, an association previously undescribed in the literature.

Current and upcoming radionuclide therapies in the direction of precision oncology: A narrative review.

As new molecular tracers are identified to target specific receptors, tissue, and tumor types, opportunities arise for the development of both diagnostic tracers and their therapeutic counterparts, termed "theranostics." While diagnostic tracers utilize positron emitters or gamma-emitting radionuclides, their theranostic counterparts are typically bound to beta and alpha emitters, which can deliver specific and localized radiation to targets with minimal collateral damage to uninvolved surrounding structures. This is an exciting time in molecular imaging and therapy and a step towards personalized and precise medicine in which patients who were either without treatment options or not candidates for other therapies now have expanded options, with tangible data showing improved outcomes. This manuscript explores the current state of theranostics, providing background, treatment specifics, and toxicities, and discusses future potential trends.

Higher SUVmax on FDG-PET is associated with shorter survival in adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is an aggressive, rare malignancy. 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography (FDG-PET) assesses tumor metabolism and glucose utilization. We hypothesized that higher maximum standard uptake value (SUVmax) is associated with decreased survival. METHODS: We performed a retrospective analysis of patients with ACC. Included patients (n = 26) had an FDG-PET scan available with a documentable SUVmax. Patients were dichotomized into "High" (≥8.4, n = 12) and "Low" (<8.4, n = 14) SUVmax. Univariate analysis and survival analysis were performed to compare groups. RESULTS: Demographics between groups were equivalent. The high SUVmax cohort demonstrated lower survival (median 479 days or 15.7 months) compared to the low group (median 1490 days or 48.6 months, p = .01). Log-Rank curve confirmed differences in survival (p = .007). CONCLUSIONS: Higher SUVmax was associated with significantly worse survival in ACC and may reflect a more aggressive phenotype. FDG-PET may provide clinically useful information to determine prognosis and treatment. Further studies should prospectively evaluate using FDG-PET/CT in ACC.

Lutetium Lu 177 vipivotide tetraxetan for metastatic castration-resistant prostate cancer.

INTRODUCTION: 177Lu-vipivotide tetraxetan is a radiopharmaceutical that selectively targets prostate-specific membrane antigen (PSMA) and delivers beta-radiations to kill prostate cancer cells. AREAS COVERED: Extensive experience outside the United States as well as randomized phase II and phase III data demonstrate that 177Lu-vipivotide tetraxetan is a safe, generally well tolerated, and effective therapy for men with mCRPC. 177Lu-vipivotide tetraxetan was approved by the FDA in March 2022 for the treatment of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) after androgen receptor pathway inhibition and taxane-based chemotherapy based on the results of the VISION trial. EXPERT OPINION: This review discusses the development and studies leading to the approval of 177Lu-vipivotide tetraxetan. In all, 177Lu-vipivotide tetraxetan is an exciting new tool in the arsenal for men with mCRPC after novel androgen pathway inhibitors and at least one taxane chemotherapy. Optimal selection of patients, sequencing of 177Lu-vipivotide tetraxetan with the other agents available to treat mCRPC, and the use of dosimetry are current areas of interest with great potential and opportunities for further individual patient optimization using the tools of theranostics.