A Bispecific Antibody That Targets the Membrane-Proximal Region of Mesothelin and Retains High Anticancer Activity in the Presence of Shed Mesothelin.

Mesothelin (MSLN) is a cell-surface protein that is expressed in many cancers, which makes it a popular target for Ab-based cancer therapy. However, MSLN is shed from cancer cells at high levels via proteases that cleave at its membrane-proximal C-terminal region. Shed MSLN accumulates in patients' fluids and tumors and can block Ab-based MSLN-targeting drugs from killing cancer cells. A previously established mAb, 15B6, binds MSLN at its protease-sensitive C-terminal region and does not bind shed MSLN. Moreover, 15B6 variable fragment (Fv)-derived chimeric antigen receptor T cells are not inhibited by shed MSLN and kill tumors in mice more effectively than mAb SS1 Fv-derived chimeric antigen receptor T cells, which bind an epitope retained in shed MSLN. In this study, we have established 15B6 Fv-derived MSLN × CD3 bispecific antibodies (BsAb) that target MSLN-expressing cancers. We identified our lead candidate BsAb 5 after screening multiple 15B6-derived BsAb formats in vitro for cytotoxic activity. BsAb 5 activates T cells to kill various cancer cell lines in a MSLN-specific manner. MSLN 296-591 His, a recombinant protein mimicking shed MSLN, does not inhibit 15B6-derived BsAb 5 but completely inhibits humanized SS1-derived BsAb 7. Furthermore, BsAb 5 inhibits and delays tumor growth and is not inhibited by MSLN 296-585 His in mice. Our findings indicate that by targeting the protease-sensitive region of MSLN, BsAb 5 has high MSLN-specific anticancer activity that is not inhibited by shed MSLN. BsAb 5 may be a promising immunotherapy candidate for MSLN-expressing cancers.

A bispecific antibody that targets the membrane-proximal region of mesothelin and retains high anticancer activity in the presence of shed mesothelin.

Mesothelin (MSLN) is a cell-surface protein that is expressed on many cancers, which makes it a popular target for antibody-based cancer therapy. However, MSLN is shed from cancer cells at high levels via proteases that cleave at its membrane-proximal C-terminal region. Shed MSLN accumulates in patient fluids and tumors and can block antibody-based MSLN-targeting drugs from killing cancer cells. A previously established monoclonal antibody (mAb), 15B6, binds MSLN at its protease-sensitive C-terminal region and does not bind shed MSLN. 15B6 variable fragment (Fv)-derived chimeric antigen receptor (CAR) T cells are not inhibited by shed MSLN and kill tumors in mice more effectively than mAb SS1 Fv-derived CAR T cells, which bind an epitope retained in shed MSLN. Here, we have established 15B6 Fv-derived MSLN x CD3 bispecific antibodies (BsAbs) that target MSLN-expressing cancers. We identified our lead candidate, BsAb 5, after screening multiple 15B6-derived BsAb formats in vitro for cytotoxic activity. BsAb 5 activates T cells to kill various cancer cell lines in a MSLN-specific manner. MSLN 296-591 His, a recombinant protein mimicking shed MSLN, does not inhibit 15B6-derived BsAb 5 but completely inhibits humanized SS1-derived BsAb 7. Furthermore, BsAb 5 inhibits and delays tumor growth and is not inhibited by MSLN 296-585 His in mice. Our findings indicate that by targeting the protease-sensitive region of MSLN, BsAb 5 has high MSLN-specific anticancer activity that is not inhibited by shed MSLN. BsAb 5 may be a promising immunotherapy candidate for MSLN-expressing cancers.

Multisociety statement on coronavirus disease 2019 (COVID-19) vaccination as a condition of employment for healthcare personnel.

This consensus statement by the Society for Healthcare Epidemiology of America (SHEA) and the Society for Post-Acute and Long-Term Care Medicine (AMDA), the Association for Professionals in Epidemiology and Infection Control (APIC), the HIV Medicine Association (HIVMA), the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP) recommends that coronavirus disease 2019 (COVID-19) vaccination should be a condition of employment for all healthcare personnel in facilities in the United States. Exemptions from this policy apply to those with medical contraindications to all COVID-19 vaccines available in the United States and other exemptions as specified by federal or state law. The consensus statement also supports COVID-19 vaccination of nonemployees functioning at a healthcare facility (eg, students, contract workers, volunteers, etc).

Scientific solution to a complex problem: physiology and multidisciplinary team improve understanding and outcome in chronic constipation and faecal incontinence.

PURPOSE: There is a lack of diagnostic credibility to direct focused management for children with chronic constipation (CC) and faecal incontinence (FI). The aim is to assess the impact of an innovative Children's Anorectal Physiology Service (CAPS) focusing on improving outcomes in children with CC/FI. METHODS: Prospective data: demographics, bowel and quality of life (QoL)/risk of distress questionnaires. Diagnostics: awake high-resolution anorectal manometry (AHRAM), endoanal ultrasound and transit marker studies (TMS). RESULTS: Total patients: 112; 66 males (59%); median 9 years (17 months to 16 years). Patient groups included: 89 (79%) had functional CC/FI; 9 (8%), Hirschsprung's disease; 12 (11%), anorectal malformations and 2 (2%), trauma. St Marks Incontinence score (SMIS) abnormal in 91 (81%) and Cleveland Constipation Score (CCS) in 101 (90%) patients. Anorectal manometry: 94 (84%) awake and 18 (17%) under anaesthesia. Play specialist input 37 (33%) patients. AHRAM abnormal 65 (58%): sphincter dysfunction 36 (32%) and altered rectal sensation: hyposensitive 22% (20/91); 21% (19/91) hypersensitive. TMS normal in 64 (57%), 17 (15%) slow transit and 27 (24%) rectal evacuatory disorder. Risk of distress in 38% and poor QoL in 55% patients which correlated with abnormal SMIS (p = 0.02). Patient/parent satisfaction improved significantly (p < 0.05). CONCLUSIONS: Scientific investigations combined with multidisciplinary team improve patient satisfaction and reduces patient self-report illness severity. A complex problem requires a scientific solution.

Monitoring tropical forest carbon stocks and emissions using Planet satellite data.

Tropical forests are crucial for mitigating climate change, but many forests continue to be driven from carbon sinks to sources through human activities. To support more sustainable forest uses, we need to measure and monitor carbon stocks and emissions at high spatial and temporal resolution. We developed the first large-scale very high-resolution map of aboveground carbon stocks and emissions for the country of Peru by combining 6.7 million hectares of airborne LiDAR measurements of top-of-canopy height with thousands of Planet Dove satellite images into a random forest machine learning regression workflow, obtaining an R2 of 0.70 and RMSE of 25.38 Mg C ha-1 for the nationwide estimation of aboveground carbon density (ACD). The diverse ecosystems of Peru harbor 6.928 Pg C, of which only 2.9 Pg C are found in protected areas or their buffers. We found significant carbon emissions between 2012 and 2017 in areas aggressively affected by oil palm and cacao plantations, agricultural and urban expansions or illegal gold mining. Creating such a cost-effective and spatially explicit indicators of aboveground carbon stocks and emissions for tropical countries will serve as a transformative tool to quantify the climate change mitigation services that forests provide.

Identification of proton-pump inhibitor drugs that inhibit Trichomonas vaginalis uridine nucleoside ribohydrolase.

Trichomonas vaginalis continues to be a major health problem with drug-resistant strains increasing in prevalence. Novel antitrichomonal agents that are mechanistically distinct from current therapies are needed. The NIH Clinical Compound Collection was screened to find inhibitors of the uridine ribohydrolase enzyme required by the parasite to scavenge uracil for its growth. The proton-pump inhibitors omeprazole, pantoprazole, and rabeprazole were identified as inhibitors of this enzyme, with IC50 values ranging from 0.3 to 14.5 µM. This suggests a molecular mechanism for the in vitro antitrichomonal activity of these proton-pump inhibitors, and may provide important insights toward structure-based drug design.

Who is using chronic acid suppression therapy and why?

OBJECTIVES: Acid suppression medications have become one of the most commonly prescribed classes of therapeutic agents. Because little data exists describing the chronic use of these agents among a general population, we sought to determine the patterns of use of proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs) in clinical practice, as well as the distribution and severity of symptoms in patients prescribed these therapies. METHODS: Pharmacy billing data from two insurers were used to identify all patients on chronic (>90 days) PPIs and H2RAs within a large, eastern Massachusetts provider network. Patient demographics, diagnoses, frequency of office visits, and information about diagnostic testing were obtained from billing databases. A questionnaire addressing recent upper GI symptoms, over-the-counter medication use, and gastroenterologist consultations was mailed to a 1,139 patient subset (35%) of eligible patients. We compared the diagnoses of patients on chronic therapy with those of the general population of the network. We also compared the frequency of symptoms and diagnostic testing between those prescribed H2RAs and PPIs. RESULTS: From a total population of 168,727 adult patients, we identified 4,684 (2.8%) prescribed chronic acid suppression therapy, with 47% taking H2RAs and 57% taking PPIs (4% filled prescriptions for both simultaneously). A relevant GI diagnosis was found using billing data for only 61% of patients, mainly for gastroesophageal reflux disease (38%) and dyspepsia (42%), with many patients carrying both diagnoses. Our survey (response rate 59%) revealed that more than 30% of responders experienced heartburn or reflux more than twice a week, and more than half experienced symptoms of dyspepsia at least once a week. Diagnostic testing was uncommon, with only 19% having undergone esophagogastroduodenoscopy within the prior 2 yr. CONCLUSIONS: Acid suppression medications were used chronically by a large number of patients within this population. A significant proportion of patients on chronic PPI or H2RA lacked definitive upper GI diagnoses in their billing data. The high symptom burden and low use of diagnostic testing indicates opportunities for improvement in the care of patients on chronic acid suppression therapy.