Coevolution of craton margins and interiors during continental break-up.

Many cratonic continental fragments dispersed during the rifting and break-up of Gondwana are bound by steep topographic landforms known as 'great escarpments'1-4, which rim elevated plateaus in the craton interior5,6. In terms of formation, escarpments and plateaus are traditionally considered distinct owing to their spatial separation, occasionally spanning more than a thousand kilometres. Here we integrate geological observations, statistical analysis, geodynamic simulations and landscape-evolution models to develop a physical model that mechanistically links both phenomena to continental rifting. Escarpments primarily initiate at rift-border faults and slowly retreat at about 1 km Myr-1 through headward erosion. Simultaneously, rifting generates convective instabilities in the mantle7-10 that migrate cratonward at a faster rate of about 15-20 km Myr-1 along the lithospheric root, progressively removing cratonic keels11, driving isostatic uplift of craton interiors and forming a stable, elevated plateau. This process forces a synchronized wave of denudation, documented in thermochronology studies, which persists for tens of millions of years and migrates across the craton at a comparable or slower pace. We interpret the observed sequence of rifting, escarpment formation and exhumation of craton interiors as an evolving record of geodynamic mantle processes tied to continental break-up, upending the prevailing notion of cratons as geologically stable terrains.

Exploring markers of immunoresponsiveness in papillary thyroid carcinoma and future treatment strategies.

BACKGROUND: The study summarizes the potential use of immunotherapy for BRAF-mutated papillary thyroid cancer (PTC) by analyzing the immune profile of City of Hope PTC patient samples and comparing them to the thyroid dataset available in the TCGA database. MATERIALS AND METHODS: PTC cases with available formalin-fixed paraffin-embedded archived tumor tissue were identified. RNA was extracted from the tumor tissue and analyzed by NanoString to evaluate their immune gene expression profile. Immunohistochemistry was used to determine the expression of immune suppressive genes and lymphocytic infiltration into the tumor tissue. Thyroid cancer cell lines (MDA-T32, MDA-T68, MDA-T85, and MDA-T120) were used to determine the correlation between the BRAF inhibition and CD274 expression. RESULTS: The study found that PTC cases with BRAF mutations had higher expression of immune checkpoint markers CD274 and CTLA4, as well as higher tumor-infiltrating lymphocytes, particularly CD4+T cells. Additionally, the study identified immunosuppressive markers expressed by tumor cells like CD73, CD276, and CD200 that could be targeted for immunotherapy. Further experiments using PTC cell lines lead to the conclusion that CD274 expression correlates with BRAF activity and that inhibitors of BRAF could potentially be used in combination with immunotherapy to treat PTC. CONCLUSIONS: These findings suggest that PTC cases with BRAF mutations or high expression may be correlated with an immune hot signature and could benefit from immunotherapeutic strategies.

Rift-induced disruption of cratonic keels drives kimberlite volcanism.

Kimberlites are volatile-rich, occasionally diamond-bearing magmas that have erupted explosively at Earth's surface in the geologic past1-3. These enigmatic magmas, originating from depths exceeding 150 km in Earth's mantle1, occur in stable cratons and in pulses broadly synchronous with supercontinent cyclicity4. Whether their mobilization is driven by mantle plumes5 or by mechanical weakening of cratonic lithosphere4,6 remains unclear. Here we show that most kimberlites spanning the past billion years erupted about 30 million years (Myr) after continental breakup, suggesting an association with rifting processes. Our dynamical and analytical models show that physically steep lithosphere-asthenosphere boundaries (LABs) formed during rifting generate convective instabilities in the asthenosphere that slowly migrate many hundreds to thousands of kilometres inboard of rift zones. These instabilities endure many tens of millions of years after continental breakup and destabilize the basal tens of kilometres of the cratonic lithosphere, or keel. Displaced keel is replaced by a hot, upwelling mixture of asthenosphere and recycled volatile-rich keel in the return flow, causing decompressional partial melting. Our calculations show that this process can generate small-volume, low-degree, volatile-rich melts, closely matching the characteristics expected of kimberlites1-3. Together, these results provide a quantitative and mechanistic link between kimberlite episodicity and supercontinent cycles through progressive disruption of cratonic keels.

Implications of updated staging system for p16+ oropharyngeal squamous cell carcinoma: Is valuable prognostic information being omitted?

BACKGROUND: This study characterized whether the updated AJCC 8th edition nodal staging system for p16+ oropharyngeal squamous cell carcinoma (OPSCC) resulted in the loss of prognostic value. METHODS: The NCDB was queried for patients with node-positive p16+ OPSCC. The prognostic impact of nodal size, nodal quantity, nodal laterality, and extracapsular extension (ECE) on overall survival (OS) was assessed. RESULTS: In the clinical cohort, inferior 5-year OS was observed in patients with more than one positive lymph node (p < 0.001; 82% vs. 86%), ECE (p < 0.001; 82% vs. 75%), or nodal size >6 cm (p < 0.001; 66% vs. 82%). In the pathologic cohort, inferior 5-year OS was observed in patients with > four positive lymph nodes (p < 0.001; 76% vs. 90%), ECE (p < 0.001; 83% vs. 92%), or largest nodal size >6 cm (p < 0.001; 81% vs. 89%). CONCLUSIONS: Simplifications in the current p16+ OPSCC staging system led to loss of prognostic information in nodal staging.

Complete mimicry: Rhabdomyosarcoma with FUS::TFCP2 fusion masquerading as carcinoma-diagnostic challenge and report of two cases.

Rhabdomyosarcomas (RMS) are malignant mesenchymal tumors with skeletal muscle differentiation which are classified into alveolar, embryonal, pleomorphic, and spindle cell/sclerosing RMS. Within the spindle cell/sclerosing RMS tumor type there is a recently recognized sub-type categorized as intraosseous spindle cell RMS with TFCP2/NCOA2 gene fusion. This rare tumor is highly aggressive with predominant involvement of the craniofacial and pelvic bones with approximately 30 cases reported to date. Histopathologic features include spindle cell and epithelioid morphology with a characteristic co-expression of epithelial markers, myogenic markers, and ALK1 expression. We report two cases of gnathic spindle cell/sclerosing RMS with FUS::TFCP2 gene fusion that were initially interpreted as carcinomas by referring institutions and later reclassified when encountered in our practice after additional work-up and molecular characterization.

Wolf in sheep's clothing - Oral proliferative verrucous leukoplakia: Progression with longitudinal molecular insights.

BACKGROUND: Oral proliferative verrucous leukoplakia (OPVL) is a chronic form of oral leukoplakia that progresses to a multifocal disease with confluent, exophytic and proliferative features. The clinical differential diagnosis for OPVL includes frictional keratosis, leukoplakia, chronic hyperplastic candidiasis, squamous papilloma, verrucous hyperplasia, verrucous carcinoma and squamous cell carcinoma. In this study, we aimed to delineate the dynamic changes in molecular signature during OPVL progression. We compare to a cohort of oral cavity keratinizing squamous cell carcinoma (OSCC) patients covering the spectrum of verrucous carcinoma to invasive squamous cell carcinoma including cytologically bland cuniculatum variant. METHODS: Samples from a large OPVL lesion that exhibited a histopathologic continuum of OPVL progression. RESULTS: Canonical hotspot TERT promoter mutations were identified in all patients. TERT C228T was dominant and mutually exclusive with TERT C250T. In patients with TERT C250T, there was concurrent PI3 point mutation. TP53 mutations were also consistently found (8/10). At the protein level, p53 was abnormal, with loss of function and gain of function. CONCLUSIONS: OPVL is a pathology that shows proximity to the gene expression profile of OSCC, highlighting signatures in common that can be important targets for drug treatment, as well as in the development of diagnostic and prognostic strategies for this disease.

Evolving mantle convection from bottom up to top down.

When it comes to convection, what goes up must come down. Or is it, what goes down must come up? The truth is it depends. Although convection must be mass balanced, there is no reason that it must be force balanced: the positive and negative buoyancy forces driving convection up and down, respectively, do not necessarily need to be balanced. The balance, or imbalance, all depends on the top and bottom boundary layers. Thus, convection in Earth's mantle depends on the temperature differences across the core-mantle boundary below and the lithosphere-asthenosphere boundary above. Convective asymmetry predominated by positive buoyancy, or bottom-up convection, would be driven by plume ascent, whereas if it were predominated by negative buoyancy, or top-down convection, it would be driven by plate subduction. Symmetric convection would balance plume ascent and plate subduction. Is mantle convection on Earth balanced, dominantly top down or bottom up, or time dependent?

Prolonged response to checkpoint inhibitor therapy in two metastatic mucoepidermoid salivary gland carcinoma cases: a research report.

Salivary gland tumors (SGTs) are heterogeneous tumors that range from benign masses to aggressive high-grade carcinomas with distant metastatic potential and limited response to chemotherapy. Mucoepidermoid carcinoma (MEC) accounts for 10% of SGTs and has a poor prognosis. In this research report, we describe two cases of metastatic high-grade MECs with prolonged response to immune checkpoint inhibitor pembrolizumab. Case 1 presented with a left neck mass, and biopsy of the parotid mass revealed MEC. The patient underwent surgical resection and adjuvant chemoradiation therapy for stage IVB disease. Post-treatment, she was found to have brain and spinal metastases and was placed on pembrolizumab. Case 2 presented with a left neck mass, and biopsy of the right parotid gland revealed MEC. Further staging demonstrated metastatic disease in the lungs, and he was placed on pembrolizumab. Both cases of MEC demonstrated prolonged extracranial responses to pembrolizumab. Although both cases reported little to no PD-L1 expression, these results demonstrate immunotherapy efficacy in advanced/metastatic MEC.

Orbital forcing of ice sheets during snowball Earth.

The snowball Earth hypothesis-that a runaway ice-albedo feedback can cause global glaciation-seeks to explain low-latitude glacial deposits, as well as geological anomalies including the re-emergence of banded iron formation and "cap" carbonates. One of the most significant challenges to snowball Earth has been sedimentological cyclicity that has been taken to imply more climate dynamics than expected when the ocean is completely covered in ice. However, recent climate models suggest that as atmospheric CO2 accumulates, the snowball climate system becomes sensitive to orbital forcing. Here we show the presence of nearly all Milankovitch (orbital) cycles preserved in stratified banded iron formation deposited during the Sturtian snowball Earth. These results provide evidence for orbitally forced cyclicity of global ice sheets that resulted in periodic oxidation of ferrous iron. Orbital glacial advance and retreat cycles provide a simple mechanism to reconcile both the sedimentary dynamics and the enigmatic survival of multicellular life during snowball Earth.

A review of nasopharyngeal swab and saliva tests for SARS-CoV-2 infection: Disease timelines, relative sensitivities, and test optimization.

Testing is an essential part of containment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This review summarizes studies for SARS-CoV-2 infection and testing. Nasopharyngeal samples are best at sensitivity detection, especially in early stages of disease and in asymptomatic individuals. Current swab processing involves a 100- to 1000-fold dilution of the patient sample. Future optimization of testing should focus on using smaller volumes of viral transport media and swab designs to increase comfort and increased viral adhesion.

Factors predictive of 90-day mortality after surgical resection for oral cavity cancer: Development of a recursive partitioning analysis for risk stratification.

BACKGROUND: Factors that influence postoperative mortality (POM) have been identified, but a predictive model to guide clinicians treating oral cavity cancer (OCC) has not been well established. METHODS: Patients with OCC undergoing upfront surgical resection were included. Primary outcome was 90-day POM (90dPOM). RESULTS: 33 845 were identified using the National Cancer Database. Rate of 90dPOM was 3.2%. Predictors of higher 90dPOM include older age, higher comorbidity scores, nonprivate insurance, lower income, treatment in an academic facility, higher T- and N-classification, radical excision, and presence of positive margins. On RPA, two high-risk (90dPOM > 10%) patient subsets were identified: patients ≥80 years of age with T3-4 disease and patients <80 years, with any comorbidity and T3-4, N2-3 disease. CONCLUSIONS: We identified a subset of patients in this cohort who are at high risk for 90dPOM. These patients may warrant additional perioperative and postoperative monitoring in addition to better preoperative assessment and screening.

Thyroid cancer diagnosis in the era of precision imaging.

Thyroid cancer affects 1.3% of the population with increasing rates of incidence over the last decade (approximately 2% per year). Although the overall prognosis is good in the differentiated subtypes, there has been a slow but steady increase in rate of deaths associated with thyroid cancer (approximately 0.7% per year over the last decade). Thyroid cancer is usually detected when: (I) patients feel a lump in the neck; (II) a routine clinical exam is performed; (III) an incidental thyroid nodule is identified on diagnostic imaging (e.g., CT neck or chest, carotid ultrasound, PET scan acquired for non-thyroid pathology). Identification of suspicious thyroid nodules results in further diagnostic work-up including laboratory assessment, further imaging, and biopsy. Accurate diagnosis is required for clinical staging and optimal patient treatment design. In this review, we aim to discuss utility of various imaging modalities and their role in thyroid cancer diagnosis and management. Additionally, we aim to highlight emerging diagnostic techniques that aim to improve diagnostic specificity and accuracy in thyroid cancer, thus paving way for precision medicine.

An Analysis and Comparison of Survival and Functional Outcomes in Oropharyngeal Squamous Cell Carcinoma Patients Treated with Concurrent Chemoradiation Therapy within City of Hope Cancer Center Sites.

Oropharyngeal squamous cell carcinoma (OPSCC) is a subset of head and neck cancers that can arise due to human papillomavirus (HPV) infection. We designed a retrospective analysis to determine differences in outcomes of OPSCC patients treated at City of Hope (COH) Cancer Center's main campus versus selected satellite sites with COH-associated faculty and facilities. Patients diagnosed with OPSCC and treated with concurrent chemoradiation therapy (n = 94) were identified and included in the study. Patients underwent treatment at the COH main campus site (n = 50) or satellite sites (n = 44). The majority of patients were Caucasian, male, and diagnosed with p16 positive stage IV locally advanced OPSCC by AJCC 7th edition. Most patients completed their prescribed cumulative radiation therapy dose and had a complete response to treatment. No significant difference in overall survival and progression-free survival was observed between the main campus and the satellite sites. Our study demonstrates successful treatment completion rates as well as comparable recurrence rates between the main campus and COH-associated satellite sites. A trend toward significant difference in feeding tube dependency at 6-months was observed. Differences in feeding tube placement and dependency rates could be addressed by the establishment of on-site supportive services in satellite sites.

Factors predicting for patient refusal of head and neck cancer therapy.

BACKGROUND: The purpose of this study was to evaluate the national rate of treatment refusal in head and neck cancer (HNC). METHODS: The National Cancer Database was queried for nonmetastatic squamous cell carcinoma of the head and neck. Oncologic therapy referred to receipt of surgery, radiotherapy, or chemotherapy. RESULTS: Compared to the 230 424 patients who received treatment, 2965 (1.3%) were reported to have refused definitive therapy. Predictors included older age, female sex, African-American/other race, nonprivate insurance, greater comorbidities, more advanced disease, and residence closer to the treating facility (P < .05). Patients with a prior history of cancer, Hispanic race, those treated at academic centers, and those from higher income counties were less likely to refuse therapy (P < .05). Patients who refused definitive therapy experienced poorer survival (median 79.1 vs 8.7 months, P < .001). CONCLUSIONS: Refusing oncologic therapy is relatively rare in HNC and appears to be multifocal in nature.

Postoperative radiation performed at the same surgical facility associated with improved overall survival in oral cavity squamous cell carcinoma.

BACKGROUND: The purpose of this analysis is to evaluate whether postoperative radiotherapy (PORT) at the same facility as surgery portends to better survival outcomes compared to PORT given at a different facility. METHODS: Patients underwent upfront surgery at the National Cancer Database reporting facility followed by PORT. PORT was coded as performed at either the same facility or at a different facility as surgery. RESULTS: A total of 10 832 patients were selected. Five-year overall survival (OS) was higher in patients undergoing PORT at the same facility: 52.5% vs 48.4% (P < 0.001). PORT performed at the same facility was associated with improved OS under multivariate (HR, 0.92; P = 0.01) and propensity score matched (hazard ratio, 0.90; P = 0.004) analyses. CONCLUSIONS: OS was better among patients with head and neck cancer who received PORT at the same facility as surgery.

Earth and Moon impact flux increased at the end of the Paleozoic.

The terrestrial impact crater record is commonly assumed to be biased, with erosion thought to eliminate older craters, even on stable terrains. Given that the same projectile population strikes Earth and the Moon, terrestrial selection effects can be quantified by using a method to date lunar craters with diameters greater than 10 kilometers and younger than 1 billion years. We found that the impact rate increased by a factor of 2.6 about 290 million years ago. The terrestrial crater record shows similar results, suggesting that the deficit of large terrestrial craters between 300 million and 650 million years ago relative to more recent times stems from a lower impact flux, not preservation bias. The almost complete absence of terrestrial craters older than 650 million years may indicate a massive global-scale erosion event near that time.

Neoproterozoic glacial origin of the Great Unconformity.

The Great Unconformity, a profound gap in Earth's stratigraphic record often evident below the base of the Cambrian system, has remained among the most enigmatic field observations in Earth science for over a century. While long associated directly or indirectly with the occurrence of the earliest complex animal fossils, a conclusive explanation for the formation and global extent of the Great Unconformity has remained elusive. Here we show that the Great Unconformity is associated with a set of large global oxygen and hafnium isotope excursions in magmatic zircon that suggest a late Neoproterozoic crustal erosion and sediment subduction event of unprecedented scale. These excursions, the Great Unconformity, preservational irregularities in the terrestrial bolide impact record, and the first-order pattern of Phanerozoic sedimentation can together be explained by spatially heterogeneous Neoproterozoic glacial erosion totaling a global average of 3-5 vertical kilometers, along with the subsequent thermal and isostatic consequences of this erosion for global continental freeboard.

Oklahoma's induced seismicity strongly linked to wastewater injection depth.

The sharp rise in Oklahoma seismicity since 2009 is due to wastewater injection. The role of injection depth is an open, complex issue, yet critical for hazard assessment and regulation. We developed an advanced Bayesian network to model joint conditional dependencies between spatial, operational, and seismicity parameters. We found that injection depth relative to crystalline basement most strongly correlates with seismic moment release. The joint effects of depth and volume are critical, as injection rate becomes more influential near the basement interface. Restricting injection depths to 200 to 500 meters above basement could reduce annual seismic moment release by a factor of 1.4 to 2.8. Our approach enables identification of subregions where targeted regulation may mitigate effects of induced earthquakes, aiding operators and regulators in wastewater disposal regions.