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The release of sterilized insects to control pest populations has been used successfully during the past 6 decades, but application of the method in vertebrates has largely been overlooked or met with failure. Here, we demonstrate for the first time in fish, that a small population of sea lamprey (Petromyzon marinus; Class Agnatha), arguably one of the most impactful invasive fish in the world, can be controlled by the release of sterilized males. Specifically, the release of high numbers of sterile males (~ 1000's) into a geographically isolated population of adult sea lamprey resulted in the first multiyear delay in pesticide treatment since treatments began during 1966. Estimates of percent reduction in recruitment of age-1 sea lamprey due to sterile male release ranged from 7 to 99.9% with the precision of the estimate being low because of substantial year-to-year variability in larval density and distribution. Additional monitoring that accounts for recruitment variability in time and space would reduce uncertainty in the degree to which sterile male release reduces recruitment rates. The results are relevant to vertebrate pest control programs worldwide, especially as technical opportunities to sterilize vertebrates and manipulate sex ratios expand., (© 2024. United States Geological Survey.)

Background: Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study., Methods: A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS)., Results: Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0-15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R 2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01-10.83), P = 0.048], PFS [HR 0.55 (0.28-1.07), P = 0.08], and OS [HR 0.42 (0.21-0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups., Conclusions: Personalized combination therapies targeting a majority of a patient's molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies., Trial Registration: I-PREDICT ( NCT02534675 ) was registered on August 25, 2015., (© 2021. The Author(s).)

It is unknown whether individuals with monoclonal B-cell lymphocytosis (MBL) are at risk for adverse outcomes associated with chronic lymphocytic leukemia (CLL), such as the risk of non-hematologic cancer. We identified all locally residing individuals diagnosed with high-count MBL at Mayo Clinic between 1999 and 2009 and compared their rates of non-hematologic cancer with that of patients with CLL and two control cohorts: general medicine patients and patients who underwent clinical evaluation with flow cytometry but who had no hematologic malignancy. After excluding individuals with prior cancers, there were 107 high-count MBL cases, 132 CLL cases, 589 clinic controls and 482 flow cytometry controls. With 4.6 years median follow-up, 14 (13%) individuals with high-count MBL, 21 (4%) clinic controls (comparison MBL P<0.0001), 18 (4%) flow controls (comparison MBL P=0.0001) and 16 (12%) CLL patients (comparison MBL P=0.82) developed non-hematologic cancer. On multivariable Cox regression analysis, individuals with high-count MBL had higher risk of non-hematologic cancer compared with flow controls (hazard ratio (HR)=2.36; P=0.04) and borderline higher risk compared with clinic controls (HR=2.00; P=0.07). Patients with high-count MBL appear to be at increased risk for non-hematologic cancer, further reinforcing that high-count MBL has a distinct clinical phenotype despite low risk of progression to CLL.

The photochemical reduction of Fe(III) complexes to Fe(II) is a well-known initiation step for the production of reactive oxygen species (ROS) in sunlit waters. Here we show a geochemical mechanism for the same in dark environments based on the tidally driven, episodic movement of anoxic groundwaters through oxidized, Fe(III) rich sediments. Sediment samples were collected from the top 5 cm of sediment in a saline tidal creek in the estuary at Murrell's Inlet, South Carolina and characterized with respect to total Fe, acid volatile sulfides, and organic carbon content. These sediments were air-dried, resuspended in aerated solution, then exposed to aqueous sulfide at a range of concentrations chosen to replicate the conditions characteristic of a tidal cycle, beginning with low tide. No detectable ROS production occurred from this process in the dark until sulfide was added. Sulfide addition resulted in the rapid production of hydrogen peroxide, with maximum concentrations of 3.85 μM. The mechanism of hydrogen peroxide production was tested using a simplified three factor representation of the system based on hydrogen sulfide, Fe(II) and Fe(III). The resulting predictive model for maximum hydrogen peroxide agreed with measured hydrogen peroxide in field-derived samples at the 95% level of confidence, although with a persistent negative bias suggesting a minor undiscovered peroxide source in sediments.

Purpose: Chronic lymphocytic leukemia (CLL) is associated with an increased risk of developing second cancers. However, it is unknown whether CLL alters the disease course of these cancers once they occur., Patients and Methods: All patients with cancers of the breast (n = 579,164), colorectum (n = 412,366), prostate (n = 631,616), lung (n = 489,053), kidney (n = 95,795), pancreas (n = 82,116), and ovary (n = 61,937) reported to the SEER program from 1990 to 2007 were identified. Overall survival (OS; death resulting from any cause) and cancer-specific survival were examined, comparing patients with and without pre-existing CLL. Cancer-specific survival was evaluated for each tumor type in a site-specific manner (eg, death resulting from breast cancer in a patient with breast cancer)., Results: Patients with cancers of the breast (hazard ratio [HR], 1.70; P < .001), colorectum (HR, 1.65; P < .001), kidney (HR, 1.54; P < .001), prostate (HR, 1.92; P < .001), or lung (HR, 1.19; P < .001) had inferior OS if they had a pre-existing diagnosis of CLL after adjusting for age, sex, race, and disease stage. These results for OS remained significant for patients with cancers of the breast, colorectum, and prostate after excluding or censoring CLL-related deaths. Cancer-specific survival was also inferior for patients with cancers of the breast (HR, 1.41; P = .005) and colorectum (HR, 1.46; P < .001) who had pre-existing CLL after adjusting for age, sex, race, and disease stage., Conclusion: Inferior OS and cancer-specific survival was observed for several common cancers in patients with pre-existing CLL. Additional studies are needed to determine the optimal management of these malignancies in patients with CLL and whether more aggressive screening or alternative approaches to adjuvant therapy are needed.

Leukemia may initially present as a peripheral neuropathy, leading to a delay in diagnosis. Leukemic infiltration of peripheral nerves, or neuroleukemiosis (NL), is exceedingly rare, with no established diagnostic or therapeutic guidelines. Five cases are presented. All patients were men with a median age of 68 years (range 46-72). Three patients had acute myeloid leukemia (AML) and two had chronic lymphocytic leukemia (CLL). In two patients, leukemia presented with peripheral nerve involvement and both were found to have positive cerebrospinal fluid (CSF) cytology, making the diagnosis AML, despite negative bone marrow and peripheral smear. All patients had painful, progressive, motor and sensory deficits. Clinical patterns were mononeuropathy (n =1), multiple mononeuropathies (n =1) and plexopathy (n =3). Magnetic resonance imaging (MRI) detected mass lesions in 4/5 cases, with avid fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) useful in all of these for following clinical disease progression. Three cases of nerve biopsy were performed, two of which were diagnostic of leukemic infiltration. Radiation treatment rapidly relieved pain in patients with mass lesions, in combination with chemotherapy. Four patients had disease relapse, four systemic and one also in peripheral nerves. These cases are discussed in the context of the broader literature.

Purpose: Rash is the most common side effect of epidermal growth factor receptor (EGFR) inhibitors and negatively impacts quality of life. This single-institution study sought to explore how rash is currently managed outside a clinical trial setting and to further characterize general clinical aspects of this rash., Methods/results: Among 4101 consecutive patients with cancer of the lung, colorectum, pancreas, and head and neck, 138 had received an EGFR inhibitor. Within this group, 96 (69%) developed a rash. Forty-nine of these patients were prescribed rash therapy, and a total of 26 different palliative regimens were used. Surprisingly, most patients, with the exception of 2, appear to have manifested evidence of rash improvement-even when unproven or disproved therapies had been prescribed. Fourteen patients stopped their EGFR inhibitor because of rash, and 11 were then able to restart. No demographic variables were able to predict rash development., Conclusion: The observation that multiple, largely unproven, anecdotal therapies are being prescribed to palliate EGFR inhibitor-induced rashes underscores the need for more rigorous, prospective palliative trials.

The epidermal growth factor receptor (EGFR) inhibitors represent a relatively new class of cancer agents that also provide new challenging side effects for cancer patients. This article reviews the clinical aspects of EGFR inhibitor-induced rash, which occurs most commonly with use of these agents, and discusses some of the challenges faced in attempting palliation treatment.

Limited proteolysis of carboxypeptidase A from bovine pancreas with subtilisin Carlsberg generates a stable intermediate, carboxypeptidase S, whose esterase and peptidase activities are increased and decreased, respectively, under standard assay conditions. Carboxypeptidase S was isolated by affinity chromatography. Sequence analysis shows that it is cleaved solely at the Ala154-Gly155 bond. Its enzymatic properties were determined under stopped-flow conditions with Dns-Gly-Ala-Phe and its ester analogue Dns-Gly-Ala-OPhe. For both substrates, the Km values are increased 30-40-fold. The kcat value for peptide hydrolysis is virtually unaffected whereas that for ester hydrolysis is increased 10-fold. The magnitude of the Km effect is equivalent to a loss of 9 kJ/mol of binding energy and likely reflects a disruption of the network of hydrogen bonds that links Tyr-248 and Arg-145 to the backbone carbonyls of Ala-154 and Gly-155. The difference in kcat effects for the two substrate classes is related to differences in the chemical nature of the rate-determining step. Product release is rate determining for catalytic hydrolysis of ester substrates, and hence, the increase in kcat indicates that dissociation of products is facilitated as a result of the Ala154-Gly155 bond scission. The changes in enzymatic activity accompanying limited proteolysis are due to conformational alterations in the vicinity of the active center of the molecule. The affinity of a monoclonal antibody, mAb 100, directed toward the antigenic determinant located between residues 209 and 218 in carboxypeptidase A is diminished considerably for carboxypeptidase S.(ABSTRACT TRUNCATED AT 250 WORDS)