bluuebunny/crossref_metadata_2025 huggingface dataset:
MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
Authors: Luo Zaili , Lu Richard
Published: June 2023

Medulloblastoma (MB) is the most common malignant childhood brain tumor, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella or human counterparts from frozen tissue nuclei5 have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group-3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin-loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs reveal potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.
MDB-36. SONIDEGIB, GANT61, AND VELIPARIB TREATMENT BOTH ALONE AND IN COMBINATION INCREASES RADIATION SENSITIVITY IN PEDIATRIC SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Price Laura , Lau Bonnie
Published: June 2023

Medulloblastoma is the most common malignant brain tumor in children, accounting for 20-25% of all pediatric brain tumors. The current standard of care includes both craniospinal and focal radiation therapy which lead to negative long term consequences in the pediatric population such as bone and tissue hypoplasia, decreased neurocognitive functioning, as well as an increased risk for secondary radiation induced cancers. Thus, there is a need for novel approaches to radiation therapy that can effectively target and kill tumor cells while minimizing radiation toxicity in healthy tissue. Here, we investigate a new approach to radiation therapy relying on two classes of therapeutic agents, Sonic Hedgehog (SHH) inhibitors and Poly (ADP-ribose) Polymerase (PARP) inhibitors. The dysregulation and constitutive activation of the SHH signaling pathway accounts for ~30% of all medulloblastomas. In addition to playing a role in tumorigenesis, the SHH pathway is known to play a role in the radiation sensitivity of various cancer types. PARP1 is known to play a key role in DNA damage repair, and it has previously been shown to affect the radiation sensitivity of pediatric brain cancers including high grade glioma, medulloblastoma, and ependymoma. We hypothesize that both inhibiting the SHH pathway at Smoothened (Smo) or Gli1 and inhibiting PARP1 will enhance medulloblastoma tumor cell killing following radiation therapy. We found that in vitro treatment with Sonidegib, GANT61, and Veliparib alone without radiation was sufficient to decrease tumor cell viability and self-renewal. When followed by radiation, pre-treatment with Sonidegib, GANT61, and Veliparib, both alone and in combination, resulted in further decreased tumor cell viability and self-renewal. These data suggest that inhibition of Smo, Gli1, or PARP1 alone or in combination is a promising therapeutic strategy for increasing the radiation sensitivity of pediatric SHH medulloblastoma.
TRLS-10. ROVER: A PHASE 1/2 STUDY OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING
Authors: Koschmann Carl , Hoffman Lindsey M , Kramm Christof M , Plant-Fox Ashley , Abdelbaki Mohamed S , Bui Ashley , Casanova Michela , Morgenstern Daniel A , Swamy Preethi , Shi Hongliang , Hong Janet , Rinne Mikael L , Chi Susan N
Published: June 2023

Pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors have poor prognoses. KIT alterations are common in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. Diffuse midline gliomas with H3K27-altered (DMG-H3K27-altered) depend on PDGFRA signaling for tumor growth. However, no KIT-/PDGFRA-targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, including DMG-H3K27-altered. The selective KIT and PDGFRA inhibitor avapritinib has demonstrated potent activity against KIT activation-loop (exon 17) and juxtamembrane (exon 11) mutants (IC50<2 nM), and PDGFRA activation-loop (D842V) mutants (IC50=0.24 nM). Cellular IC50 of wild-type PDGFRA was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios from 0.74–1.00) indicates potential for CNS antitumor activity. Avapritinib is approved to treat adults with advanced systemic mastocytosis in the USA, and in Europe after ≥1 prior systemic therapy. Avapritinib is also approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations (including D842V) in the USA, and PDGFRA D842V mutations in Europe. ROVER, a 2-part phase 1/2, multicenter, open-label study (NCT04773782), is investigating avapritinib in pediatric patients aged 2 to <18 years with R/R solid tumors dependent on KIT or PDGFRA signaling, including DMG-H3K27-altered. Objectives include safety, efficacy, and pharmacokinetics. Part 1 will enroll ≥12 patients; the primary endpoint is to determine the recommended Part 2 dose (RP2D). Part 2 will enroll ≥25 patients at the RP2D; the primary endpoint is objective response rate per RECIST v1.1 for solid tumors and Response Assessment in Neuro-Oncology for CNS tumors. Avapritinib once daily will be administered in continuous 28-day cycles. Study enrollment is planned at 26 sites in 9 countries, including North America, Europe, and Asia/Pacific.
TRLS-11. A PHASE 1 STUDY OF SAVOLITINIB IN RECURRENT, PROGRESSIVE, OR REFRACTORY MEDULLOBLASTOMA, HIGH-GRADE GLIOMA, DIFFUSE INTRINSIC PONTINE GLIOMA, AND CENTRAL NERVOUS SYSTEM (CNS) TUMORS HARBORING MET ABERRATIONS: A PEDIATRIC BRAIN TUMOR CONSORTIUM TRIAL
Authors: Salloum Ralph , Huang Jie , Stewart Clinton F , Fuller Christine , Smolarek Teresa , Lenzen Alicia , Waanders Angela J , Baxter Patiricia , Lindsay Holly , Robison Nathan , Pillay-Smiley Natasha , Partap Sonia , Fangusaro Jason , Onar-Thomas Arzu , Fouladi Maryam , Dunkel Ira J
Published: June 2023

Aberrant mesenchymal epithelial transition receptor (MET) activation leads to neoplasia, promotes invasive tumor growth, angiogenesis, and metastasis. Deregulation of MET signaling pathway is frequently observed in pediatric CNS tumors making MET inhibition a potential therapeutic target in this patient population. A phase 1 first-in-children trial of the MET inhibitor savolitinib was performed in children with recurrent, progressive or refractory medulloblastoma, high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), and other CNS tumors harboring MET aberrations. The study sought to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of savolitinib using a Rolling-6 design given orally once daily continuously, and to describe its toxicity profile and pharmacokinetics (PK). Once the MTD was established, a PK expansion cohort was opened to enrollment. This will be followed by an efficacy expansion cohort for patients whose tumors harbor activating genomic MET aberrations. Tumor tissue and blood were collected as part of correlative studies in consenting subjects. Twenty-eight patients enrolled (median age:12 years; range: 6-21); one patient was deemed ineligible, and 22 patients were evaluable for dose finding. The MTD/RP2D was 350 mg/m2 (dose level 3). Two dose limiting toxicities were reported in 2 subjects and consisted of grade 3 fatigue and grade 3 ALT elevation. The most common grade 3/4 toxicities were: neutropenia (7.7%) and lymphopenia (7.7%). One partial response was observed in a patient with recurrent HGG on dose level 1 (150 mg/m2). As of the most recent data freeze, the patient had completed 35 treatment courses. Sustained stable disease was experienced by 3 other patients with recurrent DIPG who remained on treatment for a median of 9 cycles (range: 4-24). Correlative studies are ongoing and will be presented. Savolitinib was well-tolerated in children with recurrent CNS tumors with an MTD/RP2D of 350 mg/m2. Antitumor activity was observed.
II
Authors: Wharton Edith
Published: June 2023

The hours of the Hatchard Memorial librarian were from three to five; and Charity Royall’s sense of duty usually kept her at her desk until nearly half-past four.

But she had never perceived that any practical advantage thereby accrued either to North Dormer or to...
XI
Authors: Wharton Edith
Published: June 2023

At two o’clock in the morning the freckled boy from Creston stopped his sleepy horse at the door of the red house, and Charity got out. Harney had taken leave of her at Creston River, charging the boy to drive her home. Her mind...
The Castle
Authors: Kafka Franz
Published: June 2023

A remote village covered almost permanently in snow and dominated by a castle and its staff of dictatorial, sexually predatory bureaucrats - this is the setting for Kafka’s story about a man seeking both acceptance in the village and access to the castle. Kafka breaks new ground in evoking a dense village community fraught with tensions, and recounting an often poignant, occasionally farcical love-affair. He also explores the relation between the individual and power, and asks why the villagers so readily submit to an authority which may exist only in their collective imagination.

Published only after Kafka’s death, The Castle appeared in the same decade as modernist masterpieces by Eliot, Joyce, Woolf, Mann and Proust, and is among the central works of modern literature. This translation follows the text established by critical scholarship, and manuscript variants are mentioned in the notes. The introduction provides guidance to the text without reducing the reader’s own freedom to make sense of this fascinatingly enigmatic novel.
The Secret Agent
Authors: Conrad Joseph
Published: June 2023

Mr Verloc, the secret agent, keeps a shop in London’s Soho where he lives with his wife Winnie, her infirm mother, and her idiot brother, Stevie. When Verloc is reluctantly involved in an anarchist plot to blow up the Greenwich Observatory things go disastrously wrong, and what appears to be ‘A Simple Tale’ proves to involve politicians, policemen, foreign diplomats and London’s fashionable society in the darkest and most surprising interrelations.

Based on the text which Conrad’s first English readers enjoyed, this new edition includes a critical introduction which describes Conrad’s great London novel as the realization of a ‘monstrous town’, a place of idiocy, madness, criminality, and butchery.
Through Stormy Seas
Authors: Scott Robert Falcon
Published: June 2023

The Final Preparations in New Zeland

The first three weeks of November have gone with such a rush that I have neglected my diary and can only patch it up from memory.

The dates seem unimportant, but throughout the period the officers and men of...
Home Impressions and an Excursion
Authors: Scott Robert Falcon
Published: June 2023

Impressions on returning to the Hut, April 13, 1911

In choosing the site of the hut on our Home Beach I had thought of the possibility of northerly winds bringing a swell, but had argued, first, that no heavy northerly swell had ever been...
The Return of the Sun
Authors: Scott Robert Falcon
Published: June 2023

Thursday, August 3.—We have had such a long spell of fine clear weather without especially low temperatures that one can scarcely grumble at the change which we found on waking this morning, when the canopy of stratus cloud spread over us and the wind...
Selected Stories
Authors: Mansfield Katherine
Published: June 2023

‘I was jealous of her writing. The only writing I have ever been jealous of.’ Virginia Woolf

Virginia Woolf was not the only writer to admire Mansfield’s work: Thomas Hardy, D. H. Lawrence, and Elizabeth Bowen all praised her stories, and her early death at the age of thirty-four cut short one of the finest short-story writers in the English language.

This selection covers the full range of Mansfield’s fiction, from her early satirical stories to the subtly nuanced comedy of ‘The Daughters of the Late Colonel‘ and the macabre and ominous ‘A Married Man’s Story’. The stories that pay what Mansfield calls ‘a debt of love‘ to New Zealand are as sharply etched as the European stories, and she recreates her childhood world with mordant insight. Disruption is a constant theme, whether the tone is comic, tragic, nostalgic, or domestic, echoing Mansfield's disrupted life and the fractured expressions of Modernism.

This new edition increases the selection from 27 to 33 stories and prints them in the order in which they first appeared, in the definitive texts established by Anthony Alpers.
Ethan Frome
Authors: Wharton Edith
Published: June 2023

Set against the bleak winter landscape of New England, Ethan Frome tells the story of a poor farmer, lonely and downtrodden, his wife Zeena, and her cousin, the enchanting Mattie Silver. In the playing out of this short novel's powerful and engrossing drama, Edith Wharton constructed her least characteristic and most celebrated book. In its unyielding and shocking pessimism, its bleak demonstration of tragic waste, it is a masterpiece of psychological and emotional realism.

In her introduction the distinguished critic Elaine Showalter discusses the background to the novel's composition and the reasons for its enduring success.
The Call of the Wild, White Fang, and Other Stories
Authors: London Jack
Published: June 2023

Of all Jack London’s fictions none have been so popular as his dog stories. In addition to The Call of the Wild, the epic tale of a Californian dog’s adventures during the Klondike gold rush, this edition includes White Fang, and five famous short stories - ‘Bâtard’, ‘Moon-Face’, ‘Brown Wolf’, ‘That Spot’, and ‘To Build a Fire’.
Typhoon and Other Tales
Authors: Conrad Joseph
Published: June 2023

The four tales in this volume share autobiographical origins in Conrad’s experience at sea and his exile from Poland, the country of his birth. ‘Typhoon’ is the story of a steamship and her crew beset by tempest, and of the stolid captain whose dogged courage is tested to the limit. In ‘Falk’ a taciturn young woman is bizarrely courted by a tug-boat master who is haunted by a terrible secret. ‘Amy Foster’ tells of an emigrant Pole struggling to overcome isolation and prejudice in England. The final tale, ’The Secret Sharer’, is Conrad’s most famous short story, a masterpiece of suspense and ambiguity. Giving sanctuary to a fugitive sailor, a young sea-captain risks his ship and his command in order to save him.

This revised edition uses the English first edition texts and has a new chronology and bibliography.
The Voyage Out
Authors: Woolf Virginia
Published: June 2023

The Voyage Out (1915) is the story of a rite of passage. When Rachel Vinrace embarks for South America on her father’s ship she is launched on a course of self-discovery in a modern version of the mythic voyage.

Virginia Woolf knew all too well the forms that she was supposed to follow when writing of a young lady’s entrance into the world, and she struggled to subvert the conventions, wittily and assiduously, rewriting and revising the novel many times. The finished work is not, on the face of it, a ‘portrait of the artist’. However, through The Voyage Out readers will discover Woolf as an emerging and original artist: not identified with the heroine, but present everywhere in the social satire and the lyricism and patterning of consciousness.
The Letter
Authors: Childers Erskine
Published: June 2023

I have read of men who, when forced by their calling to live for long periods in utter solitude—save for a few black faces—have made it a rule to dress regularly for dinner in order to maintain their self-respect and prevent a relapse into barbarism....
Wanted, a North Wind
Authors: Childers Erskine
Published: June 2023

Nothing disturbed my rest that night, so adaptable is youth and so masterful is nature. At times I was remotely aware of a threshing of rain and a humming of wind, with a nervous kicking of the little hull, and at one moment I dreamt...
His Chance
Authors: Childers Erskine
Published: June 2023

‘I say, Davies,’ I said, ‘how long do you think this trip will last? I’ve only got a month’s leave’.

We were standing at slanting desks in the Kiel post office, Davies scratching diligently at his letter-card, and I staring feebly at mine.

‘By Jove!’...
The Pathfinders
Authors: Childers Erskine
Published: June 2023

In the late afternoon of the second day our flotilla reached the Elbe at Brunsbiittel and ranged up in the inner basin, while a big liner, whimpering like a fretful baby, was tenderly nursed into the lock. During the delay Davies left me in charge,...
My Initiation
Authors: Childers Erskine
Published: June 2023

The yacht lay with a very slight heel (thanks to a pair of small bilge-keels on her bottom) in a sort of trough she had dug for herself, so that she was still ringed with a few inches of water, as it were with a...
Imperial Escort
Authors: Childers Erskine
Published: June 2023

Memmert gripped me, then, to the exclusion of a rival notion which had given me no little perplexity during the conversation with von Brüning. His reiterated advice that we should lose no time in picking up our anchor and chain had ended by giving me...
The Luck of the Stowaway
Authors: Childers Erskine
Published: June 2023

At Esens Station I reversed my Norden tacties, jumped out smartly, and got to the door of egress first of all, gave up my ticket, and hung about the gate of the station under cover of darkness. Fortune smiled still; there was no vehicle in...
The Education of Henry Adams
Authors: Adams Henry
Published: June 2023

As a journalist, historian and novelist born into a family that included two past presidents of the United States, Henry Adams was constantly focused on the American experiment. An immediate bestseller awarded the Pulitzer Prize in 1919, his The Education of Henry Adams (1918) recounts his own and the country’s education from 1838, the year of his birth, to 1905, incorporating the Civil War, capitalist expansion and the growth of the United States as a world power. Exploring America as both a success and a failure, contradiction was the very impetus that compelled Adams to write the Education, in which he was also able to voice his deep scepticism about mankind’s power to control the direction of history. Written with immense wit and irony, reassembling the past while glimpsing the future, Adams’s vision expresses what Henry James declared the ‘complex fate’ to be an American, and remains one of the most compelling works of American autobiography today.
Under Western Eyes
Authors: Conrad Joseph
Published: June 2023

First published in 1911, Under Western Eyes traces the experiences of Razumov, a young Russian student of philosophy who is uninvolved in politics or protest. Against his will he finds himself caught up in the aftermath of a terrorist bombing directed against the Tsarist authorities. He is pulled in different directions - by his conscience and his ambitions, by powerful opposed political forces, but most of all by personal emotions he is unable to suppress. Set in St Petersburg and Geneva, the novel is in part a critical response to Dostoevsky’s Crime and Punishment but it is also a startlingly modern book. Viewed through the ‘Western eyes’ of Conrad’s English narrator, Razumov’s story forces the reader to confront the same moral issues: the defensibility of terrorist resistance to tyranny, the loss of individual privacy in a surveillance society, and the demands thrown up by the interplay of power and knowledge.

This new edition is based on the first English edition text, and has a new chronology and bibliography.
Victory
Authors: Conrad Joseph
Published: June 2023

Victory, don’t forget, has come out of my innermost self.

Victory was the last of Conrad’s novels to be set in the Malay Archipelago. Sub-titled ‘An Island Tale’, it tells the story of Axel Heyst who, damaged by his dead father’s nihilistic philosophy, has retreated from the world of commerce and colonial exploration to live alone on the island of Samburan. But Heyst’s solitary existence ends when he rescues an English girl from her rapacious patron and takes her off to his retreat. She in turn recalls him to love and life, until the world breaks in on them once more with tragic consequences. In this love story Conrad created two of his psychologically most complex and compelling characters in a narrative of great erotic power.

This new edition uses the English first edition text and has a new chronology and bibliography.
The Sea-Wolf
Authors: London Jack
Published: June 2023

Published in 1904, and drawing on London’s own experience on board a sealing ship, The Sea-Wolf describes the struggle between the civilized and the pagan, between the values of the ruthless sea-captain, Wolf Larsen, and the moral, literary Humphrey Van Weyden.

One of his most popular novels, it also reveals London’s preoccupation with the Nietzschean idea of the superman, and his interest in the brute underlying social behaviour.
Tales of the Jazz Age
Authors: Fitzgerald F. Scott
Published: June 2023

Tales of the Jazz Age (1922) was Fitzgerald’s second collection of short stories, and it contains some of the best examples of his talent as a writer of short fiction. Often overshadowed by his major novels, Fitzgerald’s short stories demonstrate the same originality and inventive range, as he chronicles with wry and astute observation the temper of the hedonistic 1920s. In ‘May Day’ and ‘The Diamond as Big as the Ritz’, two of his greatest stories, he conjures up the spirit of the age; in other stories he adopts a variety of forms - parody, a one-act play, fantasy - with unrivalled versatility. ‘The Curious Case of Benjamin Button’, a tale of a man living his life backwards, features among the ‘Fantasies’ in Fitzgerald’s self-deprecatory Table of Contents, alongside the groupings ‘My Last Flappers’ and ‘Unclassified Masterpieces’.

In these eleven stories, Fitzgerald establishes the style that was to make him one of the greatest American writers of the twentieth-century.
Chapter III
Authors: Woolf Virginia
Published: June 2023

It is, indeed, highly unfortunate, and much to be regretted that at this stage of Orlando’s career, when he played a most important part in the public life of his country, we have least information to go upon. We know that he discharged his...
ChatGPT educates college students about sexual violence and its impact on their mental health: a proposal
Authors: Folastri Sisca , Hambali I M , Ramli M , Akbar Sa’dun , Sofyan Afriyadi
Published: June 2023

ChatGPT can be, as an interactive information platform, used to facilitate learning about the psychological effects of sexual violence. Since its approach is interactive and also that it is easily accessible, it can aid in the dissemination of information, the prevention of sexual violence and its treatment. Further, it can be incorporated into the curriculum to help raise awareness about this delicate subject and aid the affected students.
Defining Dizziness: Acknowledging Vestibular Differential in Cardiopulmonary Diagnoses
Authors: Lammers Kerry , Ludwig Daniel
Published: June 2023

This clinical perspectives article provides a comprehensive and evidence-based overview of diagnosing and treating dizziness in complex patients. These patients typically present with overlapping comorbidities and symptoms that can create difficulty in discovering an accurate diagnosis and treatment plan. Vestibular dysfunction affects over 35% of adults older than 40 years, and that prevalence significantly increases with age. Eighty-five percent of adults older than 80 years had evidence of balance/vestibular dysfunction. We believe this differential diagnosis between cardiopulmonary and vestibular dizziness transcends all rehab environments across the continuum of care. We will provide evidence for vestibular background knowledge and clinical skills that intersects with evidence regarding pharmacology and competing cardiopulmonary diagnoses to provide clinicians with the framework, skills, and knowledge to differentially diagnose dizziness across multiple care settings. In addition, we will provide examples of appropriate interdisciplinary communication to assist the clinician in decision making and best practice management.
Association between wildfires and coccidioidomycosis incidence in California, 2000–2018: a synthetic control analysis
Authors: Phillips Sophie , Jones Isabel , Sondermyer-Cooksey Gail , Yu Alexander T. , Heaney Alexandra K. , Zhou Bo , Bhattachan Abinash , Weaver Amanda K. , Campo Simon K. , Mgbara Whitney , Wagner Robert , Taylor John , Lettenmaier Dennis , Okin Gregory S. , Jain Seema , Vugia Duc , Remais Justin V. , Head Jennifer R.
Published: June 2023

Background:

The frequency and severity of wildfires in the Western United States have increased over recent decades, motivating hypotheses that wildfires contribute to the incidence of coccidioidomycosis, an emerging fungal disease in the Western United States with sharp increases in incidence observed since 2000. While coccidioidomycosis outbreaks have occurred among wildland firefighters clearing brush, it remains unknown whether fires are associated with an increased incidence among the general population.

Methods:

We identified 19 wildfires occurring within California’s highly endemic San Joaquin Valley between 2003 and 2015. Using geolocated surveillance records, we applied a synthetic control approach to estimate the effect of each wildfire on the incidence of coccidioidomycosis among residents that lived within a hexagonal buffer of 20 km radii surrounding the fire.

Results:

We did not detect excess cases due to wildfires in the 12 months (pooled estimated percent change in cases: 2.8%; 95% confidence interval [CI] = −29.0, 85.2), 13–24 months (7.9%; 95% CI = −27.3, 113.9), or 25–36 months (17.4%; 95% CI = −25.1, 157.1) following a wildfire. When examined individually, we detected significant increases in incidence following three of the 19 wildfires, all of which had relatively large adjacent populations, high transmission before the fire, and a burn area exceeding 5,000 acres.

Discussion:

We find limited evidence that wildfires drive increases in coccidioidomycosis incidence among the general population. Nevertheless, our results raise concerns that large fires in regions with ongoing local transmission of Coccidioides may be associated with increases in incidence, underscoring the need for field studies examining Coccidioides spp. in soils and air pre- and post-wildfires.
Bone marrow mesenchymal stem cell-derived exosomes carrying E3 ubiquitin ligase ITCH attenuated cardiomyocyte apoptosis by mediating apoptosis signal-regulated kinase-1
Authors: Li Xuejun , Hu Xuanyi , Chen Qiansu , Jiang Tian
Published: June 2023

Background

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes have been verified to perform an effective role in treating acute myocardial infarction (MI). Herein, we aimed to investigate the role of BMSC-derived exosomes carrying itchy E3 ubiquitin ligase (ITCH) in MI and the underlying mechanism involved.

Methods

BMSCs were isolated from rat bone marrow and exosomes were extracted using ultra-high speed centrifugation. Exosomes uptake by cardiomyoblasts was determined by PKH-67 staining. Rat cardiomyoblast cell line H9C2 was stimulated by hypoxia, as in vitro model. H9C2 cell apoptosis was determined by flow cytometry. Cell viability was examined by cell counting kit-8 assay. Western blotting was performed to determine the expression of ITCH, apoptosis signal-regulated kinase-1 (ASK1), and apoptotic-related protein cleaved-caspase 3 and Bcl-2. Ubiquitination assay was employed to measure the levels of ASK1 ubiquitination.

Results

Exosomes derived from BMSCs were endocytosed by H9C2 cardiomyoblasts. BMSC-Exo downregulated cleaved-caspase 3 expression, upregulated Bcl-2 expression, further suppressed H9C2 cell apoptosis under hypoxia treatment, meanwhile the expression of ASK1 was downregulated, and similar effects were observed in BMSC-cultured supernatant (BMSC-S). However, these effects were reversed by exosome inhibitor GW4869. BMSC-derived exosomes enhanced ASK1 ubiquitination and degradation. Mechanically, exosomes of ITCH-knockdown BMSCs promoted H9C2 cell apoptosis and upregulated ASK1 expression. Overexpression of ITCH enhanced ASK1 ubiquitination and degradation. Further, the protein expression of ASK1 and cleaved-caspase 3 was upregulated and Bcl-2 protein expression was downregulated. ITCH-knockdown BMSC exosomes increased cardiomyoblast apoptosis.

Conclusion

BMSC-derived exosomes carrying ITCH suppressed cardiomyoblast apoptosis, promoted cardiomyoblast viability, and improved myocardial injury in AMI by mediating ASK1 ubiquitination.
N-acetyltransferase 2 haplotype modifies risks for both dyslipidemia and urinary bladder cancer
Authors: Hong Kyung U. , Hein David W.
Published: June 2023

A novel haplotype in N-acetyltransferase 2 (NAT2) composed of seven non-coding variants (rs1495741, rs4921913, rs4921914, rs4921915, rs146812806, rs35246381, and rs35570672) has been linked to dyslipidemia by multiple, independent genome-wide association studies. The haplotype is located approximately 14 kb downstream of NAT2-coding region (ch8:18,272,377-18,272,881; GRCh38/hg38) and represents a non-coding, intergenic haplotype. Interestingly, the same dyslipidemia NAT2 haplotype is also linked to urinary bladder cancer risk. Dyslipidemia risk alleles are associated with rapid acetylator phenotype, whereas bladder cancer risk alleles are associated with slow acetylator, suggesting that the level of systemic NAT2 activity modifies the risk of these pathologies. We speculate that rs1495741 (and its associated haplotype) belongs to a distal regulatory element of human NAT2 gene (e.g., enhancer or silencer), and the genetic variation at the newly discovered haplotype results in a differential level of NAT2 gene expression. Understanding how this NAT2 haplotype contributes to not only urinary bladder cancer but also to dyslipidemia will ultimately help devise strategies to identify and protect susceptible individuals.
Implant Size Selection on the Basis of Period, Parity, and Age: A 22-year Retrospective Analysis of 2591 Primary Augmentation Mammoplasties
Authors: Khan Umar Daraz
Published: June 2023

Background:

The size of implants can be selected objectively or subjectively. However, there is a lack of information on whether there is a change in the trend in implant size selection or whether the parity or the age can have an impact on the implant size used.

Methods:

A retrospective study to analyze implant size selection following primary augmentation was performed. Data were divided into three groups. Group A had mammoplasties between 1999 and 2011 (group 1) and 2011 and 2022, respectively (group A2). Groups B and C were divided on the basis of age and the number of children.

Results:

Group A1 included 1902 patients and group A2 included 689 patients. Group B included three subgroups: group B1 included 1345 patients who were 18–29 years old, group B2 included 1087 patients who were 30–45 years old, and group B3 had 127 patients who were 45 years or older. Group C included four subgroups: group C1 had 956 patients without children, group C2 had 422 patients who had one child, group C3 had 716 patients who had two children, and group C4 had 453 patients who had three or more children.

Conclusions:

The data showed that there was a trend toward larger size implants, and patients with children had larger implants than nulliparous patients. There was no difference seen in implant size used when patients were compared on the basis of age.
The sex disparity in liver transplantation
Authors: Hogen Rachel , Witt Matthew Hunter , Dhanireddy Kiran
Published: June 2023

Purpose of the review

This review describes the sex disparity in liver transplantation (LT) and explains its underlying causes.

Recent findings

There is a small but persistent sex disparity in transplant rate and waitlist mortality that disappears once women are listed as Status 1. Allocation systems that could replace the Model for End Stage Liver Disease (MELD)-Na with scores less reliant on serum creatine and muscle mass have the potential to alleviate part of the sex disparity. Women perform worse on frailty assessments and are more likely to have nonalcoholic steatohepatitis (NASH). A diagnosis of NASH is compounding risk factor for frailty.

Women remain disadvantaged in their access to LT despite multiple evolutions of the allocation system. An allocation system that relies less heavily on serum creatinine could partially alleviate the sex disparity. As NASH becomes more prevalent and frailty becomes more important in listing decisions, we may also need to carefully consider differences in the manifestations of frailty between the genders.
The Association of Tube Weaning and Oral Skill Development in Infants With Tube Dependency: A Prospective Study
Authors: Pahsini Karoline , Marinschek Sabine , Reininghaus Eva Z. , Dalkner Nina , Bengesser Susanne A. , Mörkl Sabrina , Russell Marion , Russel Asa N. , Scheer Peter J. , Dunitz-Scheer Marguerite
Published: June 2023

Objective:

This study was the first of its kind by assessing oral skills development during and after applying the “Graz Model” of tube weaning.

Methods:

This prospective case series study included data of 67 (35 females, 32 males, treated from March 2018 to April 2019) tube dependent children, who participated in the effective “Graz Model” of tube weaning. Parents filled out the standardized Pediatric Assessment Scale for Severe Feeding Problems (PASSFP) prior to and immediately after completion of the program. Paired sample t tests were conducted to examine pre-to-post changes in the children’s oral skills.

Results:

The study showed that oral skills increased significantly during tube weaning PASSFP score of 24.76 (standard deviation, SD = 12.38) prior to versus 47.97 (SD = 6.98) after completion of the program. Furthermore, significant changes in their sensory and tactile perception and in their general eating behavior were observed. Children also showed reduced oral aversion symptoms and food pocketing, could enjoy their meals, and increased their food repertoire. Mealtime duration could be decreased, and parents were less anxious about their infants’ intake and less frustrated because of their children’s eating behavior.

Conclusion:

The results of this study demonstrated for the first time that tube dependent children can improve their oral skills significantly during and after their participation in the child-led approach of the “Graz model” of tube weaning.
Feasibility of Telerehabilitation-Based Pelvic Floor Muscle Training for Urinary Incontinence in People With Multiple Sclerosis: A Randomized, Controlled, Assessor-Blinded Study
Authors: Yavas Ipek , Kahraman Turhan , Sagici Ozge , Ozdogar Asiye Tuba , Yigit Pinar , Baba Cavid , Ozakbas Serkan
Published: June 2023

Background and Purpose:

Urinary incontinence is a common symptom in people with multiple sclerosis. The primary aim was to investigate feasibility of telerehabilitation-based pelvic floor muscle training (Tele-PFMT) and compare its effects on leakage episodes and pad usage with home exercise-based pelvic floor muscle training (Home-PFMT) and control groups.

Methods:

Forty-five people with multiple sclerosis with urinary incontinence were randomized into 3 groups. Tele-PFMT and Home-PFMT groups followed the same protocol for 8 weeks, but Tele-PFMT performed exercises 2 sessions/week under a physiotherapist's supervision. The control group did not receive any specific treatment. Assessments were made at baseline, weeks 4, 8, and 12. Primary outcome measures were feasibility (compliance to exercise, patient satisfaction, and number of participants included in the study), number of leakage episodes, and pad usage. Secondary outcomes included severity of urinary incontinence and overactive bladder symptoms, sexual function, quality of life, anxiety, and depression.

Results:

Participant eligibility rate was 19%. Patient satisfaction and compliance to exercise were significantly higher in Tele-PFMT than in Home-PFMT (P < 0.05). No significant differences in the change of leakage episodes and pad usage were found between Tele-PFMT and Home-PFMT. No significant differences in secondary outcomes were found between PFMT groups. Participants in both the Tele-PFMT and Home-PFMT groups had significantly better scores for some measures of urinary incontinence, and overactive bladder and quality of life in compared with the control group.

Discussion and Conclusions:

Tele-PFMT was feasible and acceptable in people with multiple sclerosis, and this mode of delivery was associated with greater exercise compliance and satisfaction compared with Home-PFMT. However, Tele-PFMT did not exhibit superiority in terms of leakage episodes and pad usage compared with Home-PFMT. A large trial comparing Home-PFMT and Tele-PFMT is warranted.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content, available at: http://links.lww.com/JNPT/A440).
Extrinsic Vascular Pathway Preservation Improves Survival in a Rat Three-Territory Flap Model Based on the Deep Circumflex Iliac Artery
Authors: Xie Tingjun , Wang Miao , Zang Mengqing , Han Tinglu , Zhu Shan , Li Shanshan , Chen Zixiang , Liu Yuanbo
Published: June 2023

Background:

Extended flaps are commonly applied for large defects. However, a postoperative flap necrosis incidence of 11% to 44% remains a major complication. Previous clinical studies have shown that maintaining the extrinsic vascular pathway (EVP) can increase the survival area of extended flaps. The authors hypothesized that preserving the EVP would improve flap survival by reducing blood resistance within the vascular territory.

Methods:

Twenty-four adult male Sprague-Dawley rats were used. Tissue samples were obtained from eight untreated rats as a baseline control. Three-territory flaps were elevated in the remaining 16 rats. The EVP was preserved or ligated. Flap perfusion was assessed immediately using indocyanine green angiography. Rats were euthanized on day 7. The flap survival area was measured using Adobe Photoshop. Hematoxylin and eosin staining, CD31 immunostaining, and Western blot analysis of vascular endothelial growth factor protein expression were used to quantitatively assess vasodilation and angiogenesis in choke zones.

Results:

Indocyanine green angiography revealed that blood could flow through the preserved EVP and perfuse the third vascular territory of the flap. EVP preservation significantly increased flap survival area (86.3%, 19.3% difference; P < 0.001), promoted vasodilation (5.0/choke zone, 3.0/choke zone difference; P = 0.013) and angiogenesis (29.3/mm2, 14.3/mm2 difference; P = 0.002), and increased vascular endothelial growth factor expression (0.6, 0.2 difference; P = 0.067) in the second choke zone.

Conclusions:

EVP preservation improves flap survival in this rat three-territory flap model. Further investigation in large-animal models is required for clinical translation.

Clinical Relevance Statement:

Although further validation in large animal models and prospective clinical trials are necessary to verify the efficacy of the authors’ hypothesis, their findings suggest that the EVP preservation procedure could provide an alternative for surgeons to create an extended flap in defect reconstruction.
Heat stress and amphibian immunity in a time of climate change
Authors: Rollins-Smith Louise A. , Le Sage Emily H.
Published: June 2023

As a class of vertebrates, amphibians, are at greater risk for declines or extinctions than any other vertebrate group, including birds and mammals. There are many threats, including habitat destruction, invasive species, overuse by humans, toxic chemicals and emerging diseases. Climate change which brings unpredictable temperature changes and rainfall constitutes an additional threat. Survival of amphibians depends on immune defences functioning well under these combined threats. Here, we review the current state of knowledge of how amphibians respond to some natural stressors, including heat and desiccation stress, and the limited studies of the immune defences under these stressful conditions. In general, the current studies suggest that desiccation and heat stress can activate the hypothalamus pituitary–interrenal axis, with possible suppression of some innate and lymphocyte-mediated responses. Elevated temperatures can alter microbial communities in amphibian skin and gut, resulting in possible dysbiosis that fosters reduced resistance to pathogens.

This article is part of the theme issue ‘Amphibian immunity: stress, disease and ecoimmunology’.
De novo genome assembly of Akanthomyces muscarius, a biocontrol agent of insect agricultural pests
Authors: Erdos Zoltan , Studholme David John , Raymond Ben , Sharma Manmohan D.
Published: June 2023

The entomopathogenic fungus Akanthomyces muscarius is commonly used in agriculture to manage insect pests. Besides its use as a commercially important biological control agent, it also presents a potential model for studying host–pathogen interactions and the evolution of virulence in a laboratory setting. Here, we describe the first high-quality genome sequence for A. muscarius. We used long- and short-read sequencing to assemble a sequence of 36.1 Mb with an N50 of 4.9 Mb. Genome annotation predicted 12347 genes, with 96.6 % completeness based on the core Hypocrealen gene set. The high-quality assembly and annotation of A. muscarius presented in this study provides an essential tool for future research on this commercially important species.
Inpatient Outcomes Of Mechanical Circulatory Support Devices and Bridging to Transplantation in Hypertrophic Cardiomyopathy
Authors: Hussain Bilal , Tarabanis Constantine , Dhulipala Vishal , Devarakonda Pradeepkumar , Maqsood Haisum , Moreno Pedro
Published: June 2023

Objective

Understand the outcomes of mechanical circulatory support devices (MCSD) and heart transplantation (HT) in patients with underlying hypertrophic cardiomyopathy (HCM).

Introduction

HCM can rarely cause severe left ventricular outflow tract obstruction and apical ballooning presenting as cardiogenic shock necessitating the use of mechanical circulatory support devices (MCSD). Data on in-hospital outcomes of HCM patients placed on MCSD and receiving HT is limited.

Methods

The National Inpatient Sample (2016-2019) was used for the retrospective analysis of patients hospitalized for MCSD and HT using ICD-10 codes. These patients were divided into two cohorts, with and without HCM, and compared in terms of in-hospital mortality, trends in mortality rates, hospitalization costs and mean length of stay.

Results

Among 254170 patients hospitalized for MCSD and HT, 12,000 patients had underlying HCM. Underlying HCM was associated with increased odds of mortality in patients receiving left ventricular assist devices (LVAD) (OR 3.06, 95% CI 1.18-7.93,p=0.02) and short-term MCSD (OR 1.8, CI 1.29-2.5, p<0.001. HCM was not associated with increased mortality in patients hospitalized for HT (OR 1.05, CI 0.42-2.6,p=0.9). Patients with HCM undergoing MCSD and HT had a longer mean length of stay (26.6 vs 14.4 days, p<0.0001), and higher mean hospitalization charges ($977797 vs $497590, p<0.0001) as compared to non-HCM patients.

Conclusion

Underlying HCM is associated with increased in-hospital mortality in patients undergoing LVAD and short-term MCSD placement. Further prospective studies are required to expand our understanding of prognosis of HCM in patients undergoing MCSD and establish management guidelines.
Neurodivergence as a risk factor for Post-Covid-19 Syndrome
Authors: Raw Rachael K. , Rees Jon , Pearson Amy , Chadwick David R.
Published: June 2023

Neurodivergent (ND) individuals (e.g., Autistic people) are more likely to experience health problems that are characterised by central sensitisation ’. Recent research suggests that a so-called ‘Long-COVID’ syndrome might also be explained by a heightened response to internal physiological stimuli, much like in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Using a standardised assessment tool, we examined whether traits associated with Autism would predict long-term COVID-19 symptoms in 267 Healthcare Workers (HCW).. Higher autistic traits predicted COVID-19 symptoms that lasting more than 12 weeks regardless of formal autism diagnosis. A personality measure also showed that negative affect was associated with experiencing COVID-19 symptoms for 4-12 weeks, though the direction of causality in this case is uncertain. Limitations of the present study are 1) the retrospective nature of COVID-19 symptom reporting; 2) likely self-selection bias given the high number of HCWs who reported long-term COVID-19 symptoms; and 3) the gender-bias towards females in our sample.