Composable computation in discrete chemical reaction networks

We study the composability of discrete chemical reaction networks (CRNs) that stably compute (i.e., with probability 0 of error) integer-valued functions $f:\mathbb{N}^d\to\mathbb{N}$. We consider output-oblivious CRNs in which the output species is never a reactant (input) to any reaction. The class of output-oblivious CRNs is fundamental, appearing in earlier studies of CRN computation, because it is precisely the class of CRNs that can be composed by simply renaming the output of the upstream CRN to match the input of the downstream CRN. Our main theorem precisely characterizes the functions $f$ stably computable by output-oblivious CRNs with an initial leader. The key necessary condition is that for sufficiently large inputs, $f$ is the minimum of a finite number of nondecreasing quilt-affine functions. (An affine function is linear with a constant offset; a quilt-affine function is linear with a periodic offset)

A Case of CCDC6-RET Fusion Mutation in Adult Acute Lymphoblastic Leukemia (ALL), a Known Activating Mutation Reported in ALL

We report the case of a patient with B-Cell Acute Lymphoblastic Leukemia (ALL) who was found to harbor a gene fusion involving the CCDC6 and RET genes. Although the RET mutations have been identified before in othermalignancies, and it is thought to represent a driver mutation in these neoplasms, it has yet to be described in ALL. The identification of known fusion genes conferring activating tyrosine kinase activity in neoplasms can suggest potential therapeutic role of tyrosine kinase inhibitors (TKI), an approach that has been exploited in several other fusion genes

Message Complexity of Population Protocols

The standard population protocol model assumes that when two agents interact, each observes the entire state of the other agent. We initiate the study of $\textit{message complexity}$ for population protocols, where the state of an agent is divided into an externally-visible $\textit{message}$ and an internal component, where only the message can be observed by the other agent in an interaction. We consider the case of $O(1)$ message complexity. When time is unrestricted, we obtain an exact characterization of the stably computable predicates based on the number of internal states $s(n)$: If $s(n) = o(n)$ then the protocol computes semilinear predicates (unlike the original model, which can compute non-semilinear predicates with $s(n) = O(\log n)$), and otherwise it computes a predicate decidable by a nondeterministic $O(n \log s(n))$-space-bounded Turing machine. We then introduce novel $O(\mathrm{polylog}(n))$ expected time protocols for junta/leader election and general purpose broadcast correct with high probability, and approximate and exact population size counting correct with probability 1. Finally, we show that the main constraint on the power of bounded-message-size protocols is the size of the internal states: with unbounded internal states, any computable function can be computed with probability 1 in the limit by a protocol that uses only $\textit{1-bit}$ messages

Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma.

The clinical deployment of immune checkpoint inhibitors (ICIs) has created a tandem drive for the identification of biomarkers linked to benefit. Comprehensive genomic profiling was performed to evaluate the frequency of genomic biomarkers of ICI response in 755 patients with advanced hepatocellular carcinoma (HCC). Median age was 62 years' old, 73% were male, 46% had extrahepatic disease, 107 had documented hepatitis C, 96 had hepatitis B and 4 patients were coinfected. Median tumor mutation burden (TMB) was 4 mutations/Mb and only 6 tumors (0.8%) were TMB-high. Out of 542 cases assessed for microsatellite instability (MSI), one (0.2%) was MSI-high and TMB-high. Twenty-seven (4%) patients had POLE/D alterations. One patient had a pathogenic POLE R762W mutation but TMB was 4 mutations/Mb. Forty percent had DNA damage response gene alterations. In a small case series (N=17) exploring the relationship between biomarkers and ICI response, one patient (TMB 15 mutations/Mb, MSI-low) had a sustained complete response to nivolumab lasting > 2 years. Otherwise there were no significant genomic or TMB differences between responders, progressors, and those with stable disease. Overall, markers of genomic instability were infrequent in this cohort. Larger clinically annotated datasets are needed to explore genomic and non-genomic determinants of ICI response in HCC

Antibody-drug conjugates, immune-checkpoint inhibitors, and their combination in advanced non-small cell lung cancer

Antibody-drug conjugates, Immune-checkpoint inhibitors; Non-small cell lung cancerConjugats de fàrmac-anticòs; Inhibidors de punts de control immunitaris; Càncer de pulmó de cèl·lules no petitesConjugados de fármaco-anticuerpo; Inhibidores de puntos de control inmunitarios; Cáncer de pulmón de células no pequeñasIntroduction Advanced non-small cell lung cancer (aNSCLC) is an incurable disease. The effort to develop treatments with more effective systemic agents continues. This has led to the FDA approval of one antibody–drug conjugate (ADC) and eight immune checkpoint inhibitors (ICIs) for patients with aNSCLC. Areas covered Due to the demonstrated efficacy of ADCs and ICIs in aNSCLC, treatment combining both agents merits attention. This article, therefore, explores the use of ADCs and ICIs in patients with NSCLC, assesses the scientific rationale for combination treatment, and provides an overview of ongoing trials. It also presents some early efficacy and safety results of such combination use. Expert opinion It is not clear whether ADC-immunotherapy has a significant impact on those with a targetable oncogenic driver alteration since targeted therapies are effective. However, in aNSCLC without a targetable oncogenic driver alteration, the combination of ADCs and ICIs has potential and remains an area of active clinical research

A time and space optimal stable population protocol solving exact majority

We study population protocols, a model of distributed computing appropriate for modeling well-mixed chemical reaction networks and other physical systems where agents exchange information in pairwise interactions, but have no control over their schedule of interaction partners. The well-studied *majority* problem is that of determining in an initial population of $n$ agents, each with one of two opinions $A$ or $B$, whether there are more $A$, more $B$, or a tie. A *stable* protocol solves this problem with probability 1 by eventually entering a configuration in which all agents agree on a correct consensus decision of $\mathsf{A}$, $\mathsf{B}$, or $\mathsf{T}$, from which the consensus cannot change. We describe a protocol that solves this problem using $O(\log n)$ states ($\log \log n + O(1)$ bits of memory) and optimal expected time $O(\log n)$. The number of states $O(\log n)$ is known to be optimal for the class of polylogarithmic time stable protocols that are "output dominant" and "monotone". These are two natural constraints satisfied by our protocol, making it simultaneously time- and state-optimal for that class. We introduce a key technique called a "fixed resolution clock" to achieve partial synchronization. Our protocol is *nonuniform*: the transition function has the value $\left \lceil {\log n} \right \rceil$ encoded in it. We show that the protocol can be modified to be uniform, while increasing the state complexity to $\Theta(\log n \log \log n)$

Pregnancy outcomes in female childhood and adolescent cancer survivors: a linked cancer-birth registry analysis

Objective: To compare birth outcomes among childhood and adolescent female cancer survivors who subsequently bear children, relative to those of women without cancer history. Design: Retrospective cohort study. Setting: 4 U.S. regions. Participants: Cancer registries identified girls <20 years, diagnosed with cancer 1973-2000. Linked birth records identified first live births after diagnosis (n=1898). Comparison subjects were selected from birth records (n=14278). Cervical/genital tract cancer cases were analyzed separately. Main Exposure: Cancer diagnosis <20 years. Outcome Measures: Infant low birth weight, preterm delivery, sex ratio, malformations, mortality, delivery method; maternal diabetes, anemia, preeclampsia. Results: Childhood cancer survivors’ infants were more likely to be preterm (relative risk [RR] 1.54, 95% CI 1.30-1.83) and weigh <2500 g (RR 1.31, 95% CI 1.10-1.57). For cervical/genital cancer patients’ offspring, estimates were 1.33 (95% CI 1.13, 1.56), and 1.29 (95% CI 1.10-1.53), respectively. There were no increased risks of malformations, infant death, or altered sex ratio, suggesting no increased germ cell mutagenicity. In exploratory analysis, bone cancer survivors had an increased risk of diabetes (RR 4.92, 95% CI 1.60-15.13), and anemia was more common among brain tumor survivors (RR 3.05, 95% CI 1.16-7.98) and childhood cancer survivors with initial treatment of chemotherapy only (RR 2.45, 95% CI 1.16-5.17). Conclusions: Infants of female childhood and adolescent cancer patients were not at increased risk of malformations or death. Increased occurrence of preterm delivery and low birth weight suggest close monitoring is warranted. Increased diabetes and anemia among sub-groups have not been reported, suggesting areas for study

Reproductive outcomes in male childhood cancer survivors: a linked cancer-birth registry analysis

OBJECTIVE: Compare the risk of reproductive and infant outcomes between male childhood cancer survivors and a population-based comparison group. DESIGN: Retrospective cohort study. SETTING: 4 U.S. regions. PARTICIPANTS: Cancer registries identified males <20 years old diagnosed with cancer 1973-2000. Linked birth certificates identified first subsequent live offspring (n=470). Comparison subjects were identified from remaining birth certificates, frequency-matched on year and age at fatherhood, and race/ethnicity (n=4150). MAIN EXPOSURE: Cancer diagnosis prior to age 20. OUTCOME MEASURES: Pregnancy and infant outcomes identified from birth certificates. RESULTS: Compared with infants born to unaffected males, offspring of cancer survivors had a borderline risk of birth weight <2500 g (RR 1.43, 95% CI 0.99-2.05), with risk associated most strongly with younger age of cancer diagnosis and exposure to any chemotherapy (RR 1.96, 95% CI 1.22-3.17) or radiotherapy (RR 1.95, 95% CI 1.14-3.35). However, they were not at risk of being born prematurely, small for gestational age, having malformations or an altered male:female sex ratio. Overall, female partners of male survivors were not more likely to have maternal complications recorded on birth records versus the comparison group. However, preeclampsia was associated with some cancers, especially central nervous system tumors (RR 3.36, 95% CI 1.63-6.90). CONCLUSIONS: Most pregnancies resulting in live births among partners of male childhood cancer survivors were not at significantly greater risk of complications versus comparison subjects. The possibility of a paternal component affected by prior cancer history influencing predisposition towards some adverse perinatal outcomes merits further investigation