A global blueberry phylogeny: Evolution, diversification, and biogeography of Vaccinieae (Ericaceae).

Vaccinieae is a morphologically diverse and species-rich (∼1430 species) tribe in Ericaceae. Although the majority of diversity is tropical, Vaccinieae are best known for temperate crops (i.e., blueberries, cranberries, and lingonberries) in Vaccinium. Vaccinium itself (∼500 species) has been previously suggested as highly polyphyletic and taxonomic boundaries among many of the other genera in the tribe remain uncertain. We assessed the evolutionary history of Vaccinieae with phylogenomic analyses based on a target-enrichment dataset containing 256 low-copy nuclear loci and 210 species representing 30 of the 35 genera in the tribe and 25 of the 29 sections of Vaccinium. We conducted time-calibrated biogeographic analyses and diversification analyses to explore the area of origin and global dispersal history of the tribe. The analysis recovered a temperate North American origin for Vaccinieae approximately 30 million years ago. Tropical diversity of Vaccinieae was inferred to result from multiple, independent movements into the tropics from north-temperate ancestors. Diversification rate increases corresponded to radiation into the Andes and SE Asia. The pseudo-10-locular ovary evolved once in the tribe from the five-locular state, coinciding with the diversification of a major clade that includes most Asian Vaccinium and the group from which commercial blueberries are derived (V. sect. Cyanococcus). A reconstruction from available chromosome counts suggests that a major polyploid event predated the evolution of nearly half the diversity of Vaccinieae. The extent of polyphyly in Vaccinium documented here supports the need for a generic reclassification of the tribe.

Recurrence factors in patients with cutaneous melanoma and positive sentinel lymph node treated in a single reference unit in Buenos Aires / Factores de recurrencia en pacientes con melanoma cu táneo y ganglio centinela positivo

Abstract Introduction : Although therapeutic advances have improved results of cutaneous melanoma (CM), senti nel node-positive patients still have substantial risk to develop recurrent disease. We aim to investigate prog nostic indicators associated with disease recurrence in positive-sentinel lymph node biopsy (SLNB) patients in a Latin-American population. Methods : Retrospective analysis of CM patients and positive-SLNB (2010-2020). Patients were divided into two groups: Group A (completion lymph node dissection, CLND), Group B (active surveillance, AS). Association of demographics, tumor data and SLN features with recurrence-free (RFS), distant metastases-free (DMFS) and melanoma specific (MSS) survival was analyzed. Results : Of 205 patients, 45 had a positive SLNB; 27(60%) belonged to Group A and 18(40%) to Group B. With a median follow-up of 36 months, 16 patients (12 in Group A and 4 in Group B) developed recurrent dis ease and estimated 5-yr RFS at any site was 60% (CI95%, 0.39 - 0.77) (44.5% in CLND group vs. 22% in AS group; P = 0.20). Estimated 5-yr DMFS and MSS: 65% (CI 95%, 0.44 - 0.81) and 73% (CI 95%, 0.59 - 0.89) with no differ ences between groups (p = 0.41 and 0.37, respectively). Independent predictors of poorer MSS were extranodal extension (ENE) and MaxSize > 2 mm of melanoma deposit in SLN. Factors independently associated with DMFS: Breslow depth > 2 mm, ENE, number (≥ 2) of posi tive SN and CLND status. Conclusion : Primary tumor and SN features in mela noma provide important prognostic information that help optimize prognosis and clinical management. AS is now the preferred approach for most positive-SLNB CM patients.

Resumen Introducción : Si bien los avances terapéuticos han permitido mejorar los resultados del melanoma cutáneo (MC), los pacientes con ganglio centinela positivo (BGCP) aún tienen riesgo elevado de desarrollar recurrencia de la enfermedad. Nuestro objetivo fue investigar in dicadores pronósticos asociados a dicho evento en una población latinoamericana. Métodos : Análisis retrospectivo de pacientes con MC y BGCP entre 2010-2020. Los pacientes se dividieron en 2 grupos: Grupo A (linfadenectomía terapéutica) y Grupo B (Vigilancia activa, VA). Se analizaron datos demográficos, tumorales y características del GC junto con sobrevida-libre de recurrencia (SLR), libre de metástasis a distancia (SLMD) y específica de melanoma (SEM). Resultados : De 205 pacientes, 45 presentaron BGCP; 27 (60%) perteneció al Grupo A y 18 (40%) al Grupo B. Con una mediana de seguimiento de 36 meses, 16 pa cientes (12 en Grupo A y 4 en Grupo B) desarrollaron enfermedad recurrente con una SLR a 5 años de 60% (IC95%: 0.39-0.77) (44.5% en Grupo B vs. 22% en Grupo A; P = 0.20). Las SLMD y SEM estimadas a 5 años fueron de 65% (CI 95%, 0.44 - 0.81) y 73% (CI 95%, 0.59 - 0.89) sin diferencias entre ambos grupos (p = 0.41 y 0.37, respec tivamente). Los predictores independientes de peor SEM fueron: extensión extranodal (ENE) y MaxSize > 2mm de depósito tumoral en GC. Los factores asociados de forma independiente con SLMD fueron Breslow >2mm, ENE, número (≥ 2) de GC positivos y el status (positividad) de la linfadenectomía. Conclusión : Características del tumor primario y del GC brindan información importante que ayuda a optimi zar el pronóstico y manejo clínico de los pacientes con MC. La VA es actualmente el abordaje de elección para la mayoría de los pacientes con BGCP.

Cancer detection rate of breast-MR in supplemental screening after negative mammography in women with dense breasts. Preliminary results of the MA-DETECT-Study after 200 participants.

BACKGROUND: Due to increased cancer detection rates (CDR), breast MR (breast MRI) can reduce underdiagnosis of breast cancer compared to conventional imaging techniques, particularly in women with dense breasts. The purpose of this study is to report the additional breast cancer yield by breast MRI in women with dense breasts after receiving a negative screening mammogram. METHODS: For this study we invited consecutive participants of the national German breast cancer Screening program with breast density categories ACR C & D and a negative mammogram to undergo additional screening by breast MRI. Endpoints were CDR and recall rates. This study reports interim results in the first 200 patients. At a power of 80% and considering an alpha error of 5%, this preliminary population size is sufficient to demonstrate a 4/1000 improvement in CDR. RESULTS: In 200 screening participants, 8 women (40/1000, 17.4-77.3/1000) were recalled due to positive breast MRI findings. Image-guided biopsy revealed 5 cancers in 4 patients (one bilateral), comprising four invasive cancers and one case of DCIS. 3 patients revealed 4 invasive cancers presenting with ACR C breast density and one patient non-calcifying DCIS in a woman with ACR D breast density, resulting in a CDR of 20/1000 (95%-CI 5.5-50.4/1000) and a PPV of 50% (95%-CI 15.7-84.3%). CONCLUSION: Our initial results demonstrate that supplemental screening using breast MRI in women with heterogeneously dense and very dense breasts yields an additional cancer detection rate in line with a prior randomized trial on breast MRI screening of women with extremely dense breasts. These findings are highly important as the population investigated constitutes a much higher proportion of women and yielded cancers particularly in women with heterogeneously dense breasts.

Recurrence factors in patients with cutaneous melanoma and positive sentinel lymph node treated in a single reference unit in Buenos Aires.

INTRODUCTION: Although therapeutic advances have improved results of cutaneous melanoma (CM), sentinel node-positive patients still have substantial risk to develop recurrent disease. We aim to investigate prognostic indicators associated with disease recurrence in positive-sentinel lymph node biopsy (SLNB) patients in a Latin-American population. METHODS: Retrospective analysis of CM patients and positive-SLNB (2010-2020). Patients were divided into two groups: Group A (completion lymph node dissection, CLND), Group B (active surveillance, AS). Association of demographics, tumor data and SLN features with recurrence-free (RFS), distant metastases-free (DMFS) and melanoma specific (MSS) survival was analyzed. RESULTS: Of 205 patients, 45 had a positive SLNB; 27(60%) belonged to Group A and 18(40%) to Group B. With a median follow-up of 36 months, 16 patients (12 in Group A and 4 in Group B) developed recurrent disease and estimated 5-yr RFS at any site was 60% (CI95%, 0.39 - 0.77) (44.5% in CLND group vs. 22% in AS group; P = 0.20). Estimated 5-yr DMFS and MSS: 65% (CI 95%, 0.44 - 0.81) and 73% (CI 95%, 0.59 - 0.89) with no differences between groups (p = 0.41 and 0.37, respectively). Independent predictors of poorer MSS were extranodal extension (ENE) and MaxSize > 2 mm of melanoma deposit in SLN. Factors independently associated with DMFS: Breslow depth > 2 mm, ENE, number (≥ 2) of positive SN and CLND status. CONCLUSION: Primary tumor and SN features in melanoma provide important prognostic information that help optimize prognosis and clinical management. AS is now the preferred approach for most positive-SLNB CM patients.

Introducción: Si bien los avances terapéuticos han permitido mejorar los resultados del melanoma cutáneo (MC), los pacientes con ganglio centinela positivo (BGCP) aún tienen riesgo elevado de desarrollar recurrencia de la enfermedad. Nuestro objetivo fue investigar indicadores pronósticos asociados a dicho evento en una población latinoamericana. Métodos: Análisis retrospectivo de pacientes con MC y BGCP entre 2010-2020. Los pacientes se dividieron en 2 grupos: Grupo A (linfadenectomía terapéutica) y Grupo B (Vigilancia activa, VA). Se analizaron datos demográficos, tumorales y características del GC junto con sobrevidalibre de recurrencia (SLR), libre de metástasis a distancia (SLMD) y específica de melanoma (SEM). Resultados: De 205 pacientes, 45 presentaron BGCP; 27 (60%) perteneció al Grupo A y 18 (40%) al Grupo B. Con una mediana de seguimiento de 36 meses, 16 pacientes (12 en Grupo A y 4 en Grupo B) desarrollaron enfermedad recurrente con una SLR a 5 años de 60% (IC95%: 0.39-0.77) (44.5% en Grupo B vs. 22% en Grupo A; P = 0.20). Las SLMD y SEM estimadas a 5 años fueron de 65% (CI 95%, 0.44 ­ 0.81) y 73% (CI 95%, 0.59 ­ 0.89) sin diferencias entre ambos grupos (p = 0.41 y 0.37, respectivamente). Los predictores independientes de peor SEM fueron: extensión extranodal (ENE) y MaxSize > 2mm de depósito tumoral en GC. Los factores asociados de forma independiente con SLMD fueron Breslow > 2mm, ENE, número (≥ 2) de GC positivos y el status (positividad) de la linfadenectomía. Conclusión: Características del tumor primario y del GC brindan información importante que ayuda a optimizar el pronóstico y manejo clínico de los pacientes con MC. La VA es actualmente el abordaje de elección para la mayoría de los pacientes con BGCP.

Protein Kinase A in neurological disorders.

Cyclic adenosine 3', 5' monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of physiological processes including gene transcription, metabolism, and synaptic plasticity. Genomic sequencing studies have identified both germline and somatic variants of the catalytic and regulatory subunits of PKA in patients with metabolic and neurodevelopmental disorders. In this review we discuss the classical cAMP/PKA signaling pathway and the disease phenotypes that result from PKA variants. This review highlights distinct isoform-specific cognitive deficits that occur in both PKA catalytic and regulatory subunits, and how tissue-specific distribution of these isoforms may contribute to neurodevelopmental disorders in comparison to more generalized endocrine dysfunction.

More With Less: Single-Incision Sling Insertion Techniques.

STUDY OBJECTIVE: To demonstrate reproducible procedures for efficient single-incision sling insertion and troubleshooting. DESIGN: Narrated video footage with stepwise demonstration of single-incision sling insertion technique with anchor system. SETTING: The mesh midurethral sling is a highly effective and safe procedure that is considered the gold standard for surgical treatment of stress urinary incontinence. Retropubic and transobturator approaches for midurethral slings have similar subjective cure rates with differing surgical risk profiles [1,2]. The retropubic route has a higher risk of injury to the bladder, nerves, and vascular structures, whereas the obturator approach carries a risk of groin or thigh pain [3-5]. Use of a single-incision sling decreases these risks and allows flexibility to perform the procedure without sedation or general anesthesia. Recent literature demonstrates similar subjective and objective success and safety of single-incision slings compared with both retropubic and transobturator approaches, although long-term data are forthcoming [5]. INTERVENTIONS: We demonstrate a stepwise approach for the insertion of a single-incision sling using a helical trocar. Easily reproducible procedures for setup and sling anchor management allow for efficient placement without assistance. In addition, we outline hand positioning, trocar management, and anchor deployment with troubleshooting techniques for potential placement difficulties. Finally, we review methods for sling tensioning to prevent complications such as voiding dysfunction and mesh or suture exposures. CONCLUSION: Given that single-incision slings are more likely to be performed under local anesthesia and are less invasive with decreased recovery time, it has the potential to become the preferred approach in the future. This video demonstrates clear and detailed steps to facilitate successful placement of the single-incision mesh midurethral sling.

[Skin cancer screening in the aging population in Saxony-Anhalt : Utilization, facilitating, and hindering factors]. / Hautkrebsfrüherkennung in der alternden Bevölkerung Sachsen-Anhalts : Inanspruchnahme sowie förderliche und hinderliche Faktoren.

BACKGROUND: Statutory skin cancer screening (gHKS) can counteract severe courses of various types of skin cancer. The example of malignant melanoma shows that screening is important for older adults in view of the average age of onset of this disease: 62 (women) and 68 years (men). For Saxony-Anhalt (ST), as a state particularly affected by demographic change, little gHKS data are available regarding its usage. OBJECTIVES: For the study, gHKS participation rates for persons aged 55 and older are presented for ST in comparison to the rest of Germany. Reasons for and barriers to participation from those eligible as well as possible fields of action are shown. MATERIALS AND METHODS: For the target group, outpatient billing data from the Central Institute for Statutory Health Insurance Physicians in Germany (Zi) on gHKS from 2011-2020 are cross-sectionally and longitudinally analysed. Guideline-based telephone interviews with 18 residents using qualitative content analysis according to Kuckartz serve to identify reasons for and barriers to the use of gHKS. RESULTS: The gHKS was rarely and irregularly used in ST and other federal states of Germany from 2011-2020; the annual utilisation rate was about 8.0% (national average: 8.4%). Between 2011 and 2020, 50% of eligible people aged 55 years and older did not participate in the gHKS. The highest utilisation rates were among men aged 70-79 years. In addition to district-specific differences, which indicate possible gaps in care, information deficits appear to be the main reason for low participation. CONCLUSION: The low utilisation of gHKS, partly due to a lack of information among those entitled to it, requires target group-specific information services.

Exploring Spinal Subarachnoid Hemorrhage: A Neurosurgical Case Series.

Spinal subarachnoid hemorrhage (SSAH) is a rare condition that can cause spinal cord or nerve root compression and permanent neurologic damage. The reported etiologies include trauma, vascular malformations or aneurysms, coagulopathies, neoplasms, autoimmune disease, and spontaneous hemorrhage. If there is evidence of neurologic deterioration, it is commonly managed as a surgical emergency, but cases of conservative management have also been reported. In this case series, we present three patients who suffered from SSAH. The first was a spontaneous cervical SSAH that occurred following cardiac catheterization, the second was a spontaneous thoracolumbar SSAH in a patient with a known history of coagulopathy, and the third was a thoracolumbar SSAH that was caused by a dural arteriovenous fistula (dAVF). All three patients exhibited neurologic deficits and thus underwent emergent decompression and hematoma evacuation. The patient with the dAVF also required open ligation of the fistula. Following surgical intervention, all three patients regained at least partial neurologic function, but one patient developed symptomatic arachnoid cysts that required further intervention. The presented case series highlights the importance and time-sensitivity of surgical decompression in patients experiencing neurologic deficits from SSAH. These cases underscore the urgency of timely neurosurgical intervention to mitigate neurologic impairment and add insights to the existing literature on this rare condition.

Current management of patients with cutaneous melanoma with a positive sentinel lymph node / Tratamiento actual de pacientes con melanoma cutáneo y ganglio centinela positivo

Abstract Introduction : Immediate completion lymph node dissection (CLND) performed in patients with a positive sentinel lymph node biopsy (SLNB) cutaneous melanoma is not associated with improved melanoma specific survival versus active surveillance (AS) using nodal ul trasound. Clinical practice experience and outcomes of AS and adjuvant therapy is now starting to be published in literature. Methods : Retrospective analysis of patients with a positive-SLNB between June/2017-February/2022. Impact of management on any-site recurrence free survival (RFS), isolated nodal recurrence (INR), distant metasta sis-free survival (DMFS) and melanoma-specific survival (MSS) was evaluated. Results : From 126 SLNB, 31 (24.6%) were positive: 24 received AS and 7 CLND. Twenty-one (68%) received ad juvant therapy (AS, 67% and CLND, 71%). With a median follow-up of 18 months, 10 patients developed recur rent disease with an estimated 2-yr RFS of 73% (CI95%, 0.55-0.86) (30% in AS group vs. 43% in dissection group; P = 0.65). Four died of melanoma with an estimated 2-yr MSS of 82% (CI 95%, 0.63-0.92) and no differences between AS and CLND groups (P = 0.21). Estimated 2-yr DMFS of the whole cohort was 76% (CI 95%, 0.57-0.88) with no differences between groups (P = 0.33). Conclusion : Active surveillance strategy has been adopted for most positive-SLNB cutaneous melanoma patients. Adjuvant therapy without immediate CLND was delivered in nearly 70% of patients. Our results align with outcomes of randomized control trials and previous real-world data.

Resumen Introducción : La linfadenectomía inmediata (LI) re alizada en pacientes con biopsia de ganglio centinela (BGC) positivo por melanoma cutáneo no está asociada a mejoría en la supervivencia libre de enfermedad vs. vigilancia activa (VA). Resultados oncológicos y experi encia en la práctica clínica con dicha conducta asociados a tratamiento adyuvante comienzan a ser publicados en la literatura. Métodos : Análisis retrospectivo incluyendo paci entes con BGC-positiva por melanoma cutáneo entre junio/2017-febrero/2022. Se evaluó impacto del manejo en: supervivencia libre de recurrencia (SLR), recurren cia ganglionar aislada (RGA), supervivencia libre de metástasis a distancia (SLMD) y supervivencia libre de enfermedad (SLE). Resultados : De 126 pacientes, 31 (24.6%) fueron positi vos: en 24 se realizó VA y en 7 LI. Veintiún pacientes (68%) recibieron tratamiento adyuvante (VA, 67% y LI, 71%). Con una media de seguimiento de 18 meses, 10 pacientes presentaron recurrencia de la enfermedad con una SLR estimada a 2 años del 73% (CI95%, 0.55-0.86) (30% en VA vs. 43% en LI; P = 0.65). Cuatro murieron de melanoma con una SLE a 2 años del 82% (CI 95%, 0.63-0.92); sin diferencia entre ambos grupos (P = 0.21). La SLMD a 2 años de toda la cohorte fue de 76% (CI 95%, 0.57-0.88; P = 0.33). Conclusión : La vigilancia activa se ha adoptado como conducta para la mayoría de los pacientes con BGC-positivo. El tratamiento adyuvante sin linfadenectomía inmediata se realizó en cerca del 70% de nuestra serie. Los resultados de nuestra serie son similares a los re portados en la literatura.

Current management of patients with cutaneous melanoma with a positive sentinel lymph node.

INTRODUCTION: Immediate completion lymph node dissection (CLND) performed in patients with a positive sentinel lymph node biopsy (SLNB) cutaneous melanoma is not associated with improved melanoma specific survival versus active surveillance (AS) using nodal ultrasound. Clinical practice experience and outcomes of AS and adjuvant therapy is now starting to be published in literature. METHODS: Retrospective analysis of patients with a positive-SLNB between June/2017-February/2022. Impact of management on any-site recurrence free survival (RFS), isolated nodal recurrence (INR), distant metastasis-free survival (DMFS) and melanoma-specific survival (MSS) was evaluated. RESULTS: From 126 SLNB, 31 (24.6%) were positive: 24 received AS and 7 CLND. Twenty-one (68%) received adjuvant therapy (AS, 67% and CLND, 71%). With a median follow-up of 18 months, 10 patients developed recurrent disease with an estimated 2-yr RFS of 73% (CI95%, 0.55-0.86) (30% in AS group vs. 43% in dissection group; P = 0.65). Four died of melanoma with an estimated 2-yr MSS of 82% (CI 95%, 0.63-0.92) and no differences between AS and CLND groups (P = 0.21). Estimated 2-yr DMFS of the whole cohort was 76% (CI 95%, 0.57-0.88) with no differences between groups (P = 0.33). CONCLUSION: Active surveillance strategy has been adopted for most positive-SLNB cutaneous melanoma patients. Adjuvant therapy without immediate CLND was delivered in nearly 70% of patients. Our results align with outcomes of randomized control trials and previous real-world data.

Introducción: La linfadenectomía inmediata (LI) realizada en pacientes con biopsia de ganglio centinela (BGC) positivo por melanoma cutáneo no está asociada a mejoría en la supervivencia libre de enfermedad vs. vigilancia activa (VA). Resultados oncológicos y experiencia en la práctica clínica con dicha conducta asociados a tratamiento adyuvante comienzan a ser publicados en la literatura. Métodos: Análisis retrospectivo incluyendo pacientes con BGC-positiva por melanoma cutáneo entre junio/2017-febrero/2022. Se evaluó impacto del manejo en: supervivencia libre de recurrencia (SLR), recurrencia ganglionar aislada (RGA), supervivencia libre de metástasis a distancia (SLMD) y supervivencia libre de enfermedad (SLE). Resultados: De 126 pacientes, 31 (24.6%) fueron positivos: en 24 se realizó VA y en 7 LI. Veintiún pacientes (68%) recibieron tratamiento adyuvante (VA, 67% y LI, 71%). Con una media de seguimiento de 18 meses, 10 pacientes presentaron recurrencia de la enfermedad con una SLR estimada a 2 años del 73% (CI95%, 0.55-0.86) (30% en VA vs. 43% en LI; P = 0.65). Cuatro murieron de melanoma con una SLE a 2 años del 82% (CI 95%, 0.63-0.92); sin diferencia entre ambos grupos (P = 0.21). La SLMD a 2 años de toda la cohorte fue de 76% (CI 95%, 0.57-0.88; P = 0.33). Conclusión: La vigilancia activa se ha adoptado como conducta para la mayoría de los pacientes con BGCpositivo. El tratamiento adyuvante sin linfadenectomía inmediata se realizó en cerca del 70% de nuestra serie. Los resultados de nuestra serie son similares a los reportados en la literatura.

Laparoscopic adrenalectomy for adrenal metastases of solid tumors.

INTRODUCTION: In patients with history of cancer adrenal metastases can be found in up to 70% of adrenal tumors detected during follow-up. Currently, laparoscopic adrenalectomy (LA) is considered the gold standard approach for benign adrenal tumors but is still controversial in malignant disease. Depending on the patient's oncological status, adrenalectomy might be a possible treatment option. Our objective was to analyze the results of LA for adrenal metastasis from solid tumors in two referral centers. METHODS: Retrospective analysis of 17 patients with non-primary adrenal malignancy treated with LA between 2007 and 2019 was performed. Demographic and primary tumor data, type of metastasis, morbidity, disease recurrence and evolution were evaluated. Patients were compared according to type of metastases: synchronous (< 6 months) vs metachronous (≥ 6 months). RESULTS: 17 patients were included. Median metastatic adrenal tumor size was 4 cm (IQR, 3-5.4). We had one conversion to open surgery. Recurrence was found in 6 patients with one recurring in the adrenal bed. The median OS was 24 (IQR, 10.5-60.5) months and 5-year OS was 61.4% (95%CI: 36.7%-81.4%). Patients with metachronous metastases had better overall survival vs. patients with synchronous metastases (87% vs. 14%, p = 0.0037). CONCLUSION: LA for adrenal metastases is a procedure associated with low morbidity and acceptable oncologic outcomes. Based on our results, seems reasonable to offer this procedure to carefully selected patients, mainly those with metachronous presentation. Indication of LA must be done on a case by case evaluation in the context of a multidisciplinary tumor board.

Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.

Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRASG12C shows increased antitumor activity in a preclinical model of KRASG12C mutant NSCLC that exhibits resistance to KRASG12C inhibitor monotherapy.

Independent effects of acute normobaric hypoxia and hypobaric hypoxia on human physiology.

The purpose of this study was to examine the effects of acute normobaric (NH, decreased FiO2) and hypobaric (HH, 4200 m ascent) hypoxia exposures compared to sea level (normobaric normoxia, NN). Tissue oxygenation, cardiovascular, and body fluid variables measured during rest and a 3-min step-test following 90-min exposures (NH, HH, NN). Muscle oxygenated hemoglobin (O2Hb) decreased, and muscle deoxygenated hemoglobin (HHb) increased environmentally independent from rest to exercise (p < 0.001). During exercise, brain O2Hb was lower at HH compared to NN (p = 0.007), trending similarly with NH (p = 0.066), but no difference between NN and NH (p = 0.158). During exercise, HR at NH (141 ± 4 beats·min-1) and HH (141 ± 3 beats·min-1) were higher than NN (127 ± 44 beats·min-1, p = 0.002), but not each other (p = 0.208). During exercise, stroke volume at HH (109.6 ± 4.1 mL·beat-1) was higher than NH (97.8 ± 3.3 mL·beat-1) and NN (99.8 ± 3.9 mL·beat-1, p ≤ 0.010) with no difference between NH and NN (p = 0.481). During exercise, cardiac output at NH (13.8 ± 0.6 L) and HH (15.5 ± 0.7 L) were higher than NN (12.6 ± 0.5 L, p ≤ 0.006) with HH also higher than NH (p = 0.001). During acute hypoxic stimuli, skeletal muscle maintains oxygenation whereas the brain does not. These differences may be mediated by environmentally specific cardiovascular compensation. Thus, caution is advised when equating NH and HH.

Interleukin-4 receptor alpha signaling regulates monocyte homeostasis.

Interleukin-4 (IL-4) and its receptors (IL-4R) promote the proliferation and polarization of macrophages. However, it is unknown if IL-4R also influences monocyte homeostasis and if steady state IL-4 levels are sufficient to affect monocytes. Employing full IL-4 receptor alpha knockout mice (IL-4Rα-/- ) and mice with a myeloid-specific deletion of IL-4Rα (IL-4Rαf/f LysMcre ), we show that IL-4 acts as a homeostatic factor regulating circulating monocyte numbers. In the absence of IL-4Rα, murine monocytes in blood were reduced by 50% without altering monocytopoiesis in the bone marrow. This reduction was accompanied by a decrease in monocyte-derived inflammatory cytokines in the plasma. RNA sequencing analysis and immunohistochemical staining of splenic monocytes revealed changes in mRNA and protein levels of anti-apoptotic factors including BIRC6 in IL-4Rα-/- knockout animals. Furthermore, assessment of monocyte lifespan in vivo measuring BrdU+ cells revealed that the lifespan of circulating monocytes was reduced by 55% in IL-4Rα-/- mice, whereas subcutaneously applied IL-4 prolonged it by 75%. Treatment of human monocytes with IL-4 reduced the amount of dying monocytes in vitro. Furthermore, IL-4 stimulation reduced the phosphorylation of proteins involved in the apoptosis pathway, including the phosphorylation of the NFκBp65 protein. In a cohort of human patients, serum IL-4 levels were significantly associated with monocyte counts. In a sterile peritonitis model, reduced monocyte counts resulted in an attenuated recruitment of monocytes upon inflammatory stimulation in IL-4Rαf/f LysMcre mice without changes in overall migratory function. Thus, we identified a homeostatic role of IL-4Rα in regulating the lifespan of monocytes in vivo.

Saturable Absorption of Free-Electron Laser Radiation by Graphite near the Carbon K-Edge.

The interaction of intense light with matter gives rise to competing nonlinear responses that can dynamically change material properties. Prominent examples are saturable absorption (SA) and two-photon absorption (TPA), which dynamically increase and decrease the transmission of a sample depending on pulse intensity, respectively. The availability of intense soft X-ray pulses from free-electron lasers (FELs) has led to observations of SA and TPA in separate experiments, leaving open questions about the possible interplay between and relative strength of the two phenomena. Here, we systematically study both phenomena in one experiment by exposing graphite films to soft X-ray FEL pulses of varying intensity. By applying real-time electronic structure calculations, we find that for lower intensities the nonlinear contribution to the absorption is dominated by SA attributed to ground-state depletion; our model suggests that TPA becomes more dominant for larger intensities (>1014 W/cm2). Our results demonstrate an approach of general utility for interpreting FEL spectroscopies.

Bilateral adrenalectomy in the context of primary adrenal insufficiency due to colorectal cancer metastasis.

Introduction: Adrenal glands are a common site of metastasis for several types of malignancies. Nevertheless, bilateral metastasis leading to adrenal insufficiency is a very rare presentation. Presentation of case: We present a 62-year-old woman with previous history of colorectal cancer and bilateral adrenal metastasis associated with primary adrenal insufficiency. The patient underwent bilateral open adrenalectomy after a multidisciplinary tumour board evaluation. Conclusion: The incidence of adrenal insufficiency may be underestimated in patients with a history of cancer. Adrenal function must be evaluated in those patients presenting with bilateral adrenal masses and hormonal replacement therapy should be considered, if appropriate. In selected cases, bilateral adrenalectomy can give a possible therapeutic option for patients with confined disease to the adrenal glands.

Outcomes after laparoscopic adrenalectomy for unilateral primary aldosteronism.

Unilateral primary aldosteronism (PA) is the most common surgically correctable cause of hypertension. Determination of success after laparoscopic adrenalectomy (LA) is limited by the lack of standardized criteria. We sought to evaluate the surgical recurrence and functional outcomes of LA in patients with Conn's syndrome applying the primary aldosteronism surgical outcome (PASO) Criteria. Descriptive observational analysis of patients treated with LA due to confirmed u nilateral Conn's syndrome between May 2007 and August 2020: Twenty patients were included in the cohort; 16 patients had TLA and other four PLA [58% male, median age 47 (IQR: 44-59.5) years and median follow-up of 64 (IQR: 2-156) ] months. Median tumor size was 1.2 (0.8-1.8) cm. No conversions to open surgery were recorded and the overall morbidity of the series was 1/20. No surgical or biochemical recurrence was observed. Five patients were excluded from the analysis of functional results due to lack of follow-up. According to the PASO criteria, complete, partial, and no success were observed in 8/15, 6/15, and 1/15, respectively. The surgical treatment of the disease is supported by the literature, and we were able to reproduce the results of other series. The use of standardized and reproducible criteria to assess its functional results would be essential for a more complete and integrated evaluation of adrenal surgery.

El hiperaldosteronismo primario es la causa más frecuente de hipertensión secundaria pasible de tratamiento quirúrgico. La determinación del éxito de la adrenalectomía laparoscópica (AL), actualmente, está limitada por la falta de criterios estandarizados. Buscamos evaluar la tasa de recurrencia quirúrgica y los resultados funcionales de la AL en pacientes con Síndrome de Conn aplicando los criterios PASO (primary aldosteronism surgical outcome). Análisis descriptivo y observacional de pacientes tratados con AL en contexto de síndrome de Conn unilateral confirmado, entre Mayo-2007 y Agosto-2020. Se incluyeron 20 pacientes en el estudio; 16 pacientes tratados mediante AL total y 4 con AL parcial (55% hombres, edad mediana de 47 (IQR: 44-59.5) años y mediana de seguimiento 64 (IQR: 2-156) meses. La mediana de tamaño tumoral fue de 1.2 (0.8-1.8) cm. No se registraron conversiones a cirugía abierta y la morbilidad global de la serie: 1/20. No se observó recurrencia quirúrgica o bioquímica. Se excluyeron 5 pacientes en el análisis de resultados funcionales por falta de seguimiento. Según los criterios PASO, se observó un éxito completo, parcial y ausente en 8/15, 6/15 y 1/15, respectivamente. El tratamiento quirúrgico de la enfermedad es avalado por la literatura y pudimos reproducir los resultados de otras series. El uso estandarizado y reproducible de criterios para valorar sus resultados funcionales sería fundamental para una evaluación más completa e integrada de la cirugía suprarrenal.

Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

Outcomes after laparoscopic adrenalectomy for unilateral primary aldosteronism / Resultados luego de adrenalectomía laparoscópica en hiperaldosteronismo primario unilateral

Abstract Unilateral primary aldosteronism (PA) is the most common surgically correctable cause of hypertension. Determination of success after laparoscopic adrenalectomy (LA) is limited by the lack of standardized criteria. We sought to evaluate the surgical recurrence and functional outcomes of LA in patients with Conn's syndrome applying the primary aldosteronism surgical outcome (PASO) Criteria. Descriptive obser vational analysis of patients treated with LA due to confirmed u nilateral Conn's syndrome between May 2007 and August 2020: Twenty patients were included in the cohort; 16 patients had TLA and other four PLA [58% male, median age 47 (IQR: 44-59.5) years and median follow-up of 64 (IQR: 2-156) ] months. Median tumor size was 1.2 (0.8-1.8) cm. No conversions to open surgery were recorded and the overall morbidity of the series was 1/20. No surgical or biochemical recurrence was observed. Five patients were excluded from the analysis of functional results due to lack of follow-up. According to the PASO criteria, complete, partial, and no success were observed in 8/15, 6/15, and 1/15, respectively. The surgical treatment of the disease is supported by the literature, and we were able to reproduce the results of other series. The use of standardized and reproducible criteria to assess its functional results would be essential for a more complete and integrated evaluation of adrenal surgery.

Resumen El hiperaldosteronismo primario es la causa más frecuente de hipertensión secundaria pasible de tratamiento quirúrgico. La determinación del éxito de la adrenalectomía laparoscópica (AL), actualmente, está limitada por la falta de criterios estandarizados. Buscamos evaluar la tasa de recurrencia quirúrgica y los resultados funcionales de la AL en pacientes con Síndrome de Conn aplicando los criterios PASO (primary aldosteronism surgical outcome). Análisis descriptivo y observacional de pacientes tratados con AL en contexto de síndrome de Conn unilateral confirmado, entre Mayo-2007 y Agosto-2020. Se incluyeron 20 pacientes en el estudio; 16 pacientes tratados mediante AL total y 4 con AL parcial (55% hombres, edad mediana de 47 (IQR: 44-59.5) años y mediana de seguimiento 64 (IQR: 2-156) meses. La mediana de tamaño tumoral fue de 1.2 (0.8-1.8) cm. No se registraron conversiones a cirugía abierta y la morbilidad global de la serie: 1/20. No se observó recurrencia quirúrgica o bioquímica. Se excluyeron 5 pacientes en el análisis de resultados funcionales por falta de seguimiento. Según los criterios PASO, se observó un éxito completo, parcial y ausente en 8/15, 6/15 y 1/15, respectivamente. El tratamiento quirúrgico de la enfermedad es avalado por la literatura y pudimos reproducir los resultados de otras series. El uso estandarizado y reproducible de criterios para valorar sus resul tados funcionales sería fundamental para una evaluación más completa e integrada de la cirugía suprarrenal.

Controversies in regenerative medicine: should knee joint osteoarthritis be treated with mesenchymal stromal cells?

Knee joint osteoarthritis is a complex immunological and degenerative disease. Current treatment strategies fail to alter its progression. Mesenchymal stromal cell (MSC) therapy for osteoarthritis has been object of research for more than 30 years. The aim of MSC therapy is intended to be holistic, with regeneration of all affected knee joint structures. The paracrine effect of the MSC secretome has been shown to be central for the regenerative capacity of MSCs. Activation of local knee-joint-specific MSCs leads to an immunomodulatory, anti-catabolic, anti-apoptotic and chondrogenic stimulus. Preclinical models have demonstrated the symptom- and disease-modifying effects of MSC therapy. At the bedside, there is evidence that autologous and allogeneic MSC therapy shows significant improvement in symptom-modifying and functional outcome. Despite this, a variety of contradictory clinical outcomes are available in the literature. The effectiveness of MSC therapy is still unclear, although there have been promising results. Regarding the diversity of cell sources, isolation, culture protocols and other factors, a comparison of different studies is difficult. Clinical translation of disease-modifying effects has not yet been shown. This narrative review presents a controversial overview of the current preclinical and clinical studies on MSC therapy in knee joint osteoarthritis.