Rediscovering, Reevaluating, and Restoring Lost River-Wetland Corridors

River-wetland corridors form where a high degree of connectivity between the surface (rheic) and subsurface (hyporheic) components of streamflow creates an interconnected system of channels, wetlands, ponds, and lakes. River-wetland corridors occur where the valley floor is sufficiently wide to accommodate a laterally unconfined river planform that may feature morphologically complex, multi-threaded channels with vegetated bars, islands, and floodplains. River-wetland corridors can develop anywhere there is valley expansion along a drainage network, from the headwaters to estuaries or deltas, and they are found across all latitudes and within all biomes and hydroclimates. River-wetland corridors may be longitudinally continuous but are commonly interspersed with single-thread reaches in narrower portions of the valley. The development and persistence of river-wetland corridors is driven by combinations of geologic, biotic, and geomorphic processes that create a river environment that is diverse, heterogeneous, patchy, and dynamically stable, and within which patterns of flow, sediment features, and habitats shift continually. Hence, we describe these polydimensional river corridors as “kaleidoscope rivers.” Historically, river-wetland corridors were pervasive in wide, alluvial valley reaches, but their presence has been so diminished worldwide (due to a diverse range of anthropogenic activities and impacts) that the general public and even most river managers are unaware of their former pervasiveness. Here, we define river-wetland corridors as a river type; review paleoenvironmental and historical records to establish their past ubiquity; describe the geologic, biotic, and geomorphic processes responsible for their formation and persistence; and provide examples of river-wetland corridor remnants that still survive. We close by highlighting the significance of the diverse river functions supported by river-wetland corridors, the consequences of diminution and neglect of this river type, and the implications for river restoration

Kinase-Impaired BTK Mutations Are Susceptible to Clinical-Stage BTK and IKZF1/3 Degrader NX-2127

INTRODUCTION: Bruton’s tyrosine kinase (BTK) is a nonreceptor kinase in the B cell receptor (BCR) signaling cascade critical for B cell survival. As such, chronic lymphocytic leukemia (CLL) and other B cell cancers are sensitive to inhibition of BTK. Covalent and noncovalent inhibitors of BTK have revolutionized the treatment of these cancers. Therefore, understanding mechanisms by which acquired mutation in BTK confer drug resistance and developing new therapies to overcome resistance are critically important. RATIONALE: We recently discovered BTK mutations that confer resistance across covalent and noncovalent BTK inhibitors. In this study, we found that a group of these mutants impair BTK kinase activity despite still enabling downstream BCR signaling. We therefore set out to understand the nonenzymatic functions of BTK and explored targeted protein degradation to overcome the oncogenic scaffold function of mutant BTK. This effort included evaluation of BTK degradation in patients with CLL treated in a phase 1 clinical trial of NX-2127, a first-in-class BTK degrader (NCT04830137). RESULTS: BTK enzymatic activity assays revealed that drug resistance mutations in BTK fall into two distinct groups: kinase proficient and kinase impaired. Immunoprecipitation mass spectrometry of kinase-impaired BTK L528W (Leu528→Trp) revealed a scaffold function of BTK with downstream signaling and survival dependent on surrogate kinases that bind to kinase-impaired BTK proteoforms. To target the nonenzymatic functions of BTK, we developed NX-2127, a heterobifunctional molecule that engages the ubiquitin-proteasome system to simultaneously bind both BTK and the cereblon E3 ubiquitin ligase complex, inducing polyubiquitination and proteasome-dependent degradation of IKZF1/3 and all recurrent drug-resistant forms of mutant BTK. The activity of NX-2127 on BTK degradation was further demonstrated in patients with CLL treated in a phase 1 clinical trial of NX-2127, where \u3e80% BTK degradation was achieved and clinical responses were also seen in 79% of evaluable patients, independent of mutant BTK genotypes. CONCLUSION: We identified that BTK inhibitor resistance mutations fall into two distinct functional categories. Kinase-impaired BTK mutants disable BTK kinase activity while promoting physical interactions with other kinases to sustain downstream BCR signaling. This scaffold function of BTK was disrupted by NX-2127, a potent BTK degrader, which showed promising responses for patients with relapsed and refractory CLL, independently of mutant BTK functional category

A Multicenter Pilot Evaluation of the National Institutes of Health Chronic Graft-versus-Host Disease (cGVHD) Therapeutic Response Measures: Feasibility, Interrater Reliability, and Minimum Detectable Change

The lack of standardized criteria for measuring therapeutic response is a major obstacle to the development of new therapeutic agents for chronic graft-versus-host disease (cGVHD). National Institutes of Health (NIH) consensus criteria for evaluating therapeutic response were published in 2006. We report the results of four consecutive pilot trials evaluating the feasibility and estimating the inter-rater reliability and minimum detectable change of these response criteria

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation

From medicine to art: Nils Paul Larsen (1890--1964)

Nils Paul Larsen (1922-1964) was a significant transitional figure in Hawai'i as it was changing from the plantation era to a modem Pacific community. Larsen, who lived in Hawai'i from 1922 until his death in 1964, was recognized in varying degrees as a physician, director, researcher, writer, historian, politician, artist, playwright, inventor, association president, decorated war hero, Swedish consul, honorary kahuna, and Congressional delegate. Larsen was especially acknowledged for his instrumental role in advancing plantation medicine and elevating public health in Hawai'i as a pathologist and Director of the Queen's Hospital. He used his professional influence to raise public awareness through numerous publications and associations in the field of health. His medical interests emphasized the need for better nutrition, notably with regard to infants and plantation workers. He was also involved with educational measures related to population control, sanitation, and industrial medicine. Larsen became President of the Honolulu Print Makers Association and was nationally recognized for his original etchings. His artistic sensibilities centered on local scenery and nature themes. His etchings often reflected a social and cultural sensitivity that suggested ambivalence toward modernity and the Western impulse toward technology and development. In the course of his many-sided career Larsen championed the cause of social justice. Among his interests were traditional Hawaiian herbal and medicinal practices that he concluded were superior to those of the early missionaries. His immersion in this line of study led him to the status of an honorary kahuna. There is ultimately a compelling contrast between Larsen's role as a scientist and empiricist and his capacity to appreciate the influence ofnontraditional medical practices. Larsen's political desires led him to accept the appointment as Swedish Consul. He advocated the change from Territorial status to statehood for Hawai'i and, in 1960, took an active role as a delegate in the Constitutional Convention to assist in the writing of the Constitution. His devotion to world unity led him to attempt to springboard the Hawai'i chapter of the World Federation, a group hoping to unite the nations ofthe globe in a "more perfect union.

Phase I Escalation and Expansion Study of Bemarituzumab (FPA144) in Patients With Advanced Solid Tumors and FGFR2b-Selected Gastroesophageal Adenocarcinoma

PURPOSETo evaluate the safety, pharmacokinetics, and preliminary activity of bemarituzumab in patients with FGFR2b-overexpressing gastric and gastroesophageal junction adenocarcinoma (GEA).PATIENTS AND METHODSFPA144-001 was a phase I, open-label, multicenter trial consisting of the following 3 parts: part 1a involved dose escalation in patients with recurrent solid tumors at doses ranging from 0.3 to 15 mg/kg; part 1b involved dose escalation in patients with advanced-stage GEA; and part 2 involved dose expansion in patients with advanced-stage GEA that overexpressed FGFR2b at various levels (4 cohorts; high, medium, low, and no FGFR2b overexpression) and 1 cohort of patients with FGFR2b-overexpressing advanced-stage bladder cancer.RESULTSSeventy-nine patients were enrolled; 19 were enrolled in part 1a, 8 in part 1b, and 52 in part 2. No dose-limiting toxicities were reported, and the recommended dose was identified as 15 mg/kg every 2 weeks based on safety, tolerability, pharmacokinetic parameters, and clinical activity. The most frequent treatment-related adverse events (TRAEs) were fatigue (17.7%), nausea (11.4%), and dry eye (10.1%). Grade 3 TRAEs included nausea (2 patients) and anemia, neutropenia, increased AST, increased alkaline phosphatase, vomiting, and an infusion reaction (1 patient each). Three (10.7%) of 28 patients assigned to a cohort receiving a dose of >= 10 mg/kg every 2 weeks for >= 70 days reported reversible grade 2 corneal TRAEs. No TRAEs of grade >= 4 were reported. Five (17.9%; 95% CI, 6.1% to 36.9%) of 28 patients with high FGFR2b-overexpressing GEA had a confirmed partial response.CONCLUSIONOverall, bemarituzumab seems to be well tolerated and demonstrated single-agent activity as late-line therapy in patients with advanced-stage GEA. Bemarituzumab is currently being evaluated in combination with chemotherapy in a phase III trial as front-line therapy for patients with high FGFR2b-overexpressing advanced-stage GEA