Autoimmune diabetes induced by the beta-cell toxin STZ. Immunity to the 60-kDa heat shock protein and to insulin

Administered at a suitably low dose, the toxin streptozotocin (STZ) can trigger an autoimmune process leading to destruction of the beta-cells of the pancreatic islets. In this study, we examined specific immunological reactions in mice before and during the development of STZ-induced autoimmune diabetes. We now report that the development of spontaneous autoantibodies to insulin can serve as a marker of susceptibility to a low dose of STZ. Susceptible male mice of the C57BL/KsJ strain manifested such anti-insulin antibodies, and resistant female mice did not. Administration of a low dose of STZ (five daily doses each of 30 mg/kg) induced transient hyperglycemia approximately 20-30 days later, which temporarily remitted but was followed by intractable diabetes approximately 2.5 months later. The diabetogenic process triggered by the low dose of STZ was associated with an increase in the level of anti-insulin antibodies bearing the Dana and Micha (DM) idiotype, later followed by the appearance of anti-idiotypic antibodies that peaked before the onset of diabetes. Antibodies and T-cells reactive to hsp60 (heat shock protein) were triggered by the low-dose STZ administration and persisted throughout the period that preceded clinical diabetes. T-cells reactive to the p277 peptide of hsp60 were also observed. Finally, active immunization to hsp60 caused transient hyperglycemia by itself and also aggravated the hyperglycemia induced by low-dose STZ. Thus, autoantibodies to insulin can indicate susceptibility to a toxic trigger of diabetes, and a low dose of a toxin can activate the insulin and hsp60 autoimmunity that has been detected previously in the spontaneous autoimmune diabetes of NOD strain mice.     

A Comparison of Free BDDs and Transformed BDDs

Ordered binary decision diagrams (OBDDs) introduced by Bryant (IEEE Trans. on Computers, Vol. 35, pp. 677–691, 1986) have found a lot of applications in verification and CAD. Their use is limited if the OBDD size of the considered functions is too large. Therefore, a variety of generalized BDD models has been presented, among them FBDDs (free BDDs) and TBDDs (transformed BDDs). Here the quite tight relations between these models are revealed and their advantages and disadvantages are discussed.     

A note on classes of complements and the LBA problem

Summary The complements of an AFL form an AFL if and only if is closed under length-preserving universal quantification. The complements of the context-sensitive languages form a principal AFL with a hardest set L ₁. The context-sensitive languages are closed under complementation if and only if L ₁ is context-sensitive.This research was supported in part by the National Science Foundation under Grants MCS76-10076 and DCR74-15091     

Amounts of nondeterminism in finite automata

Summary The amount of nondeterminism in a nondeterministic finite automaton (NFA) is measured by counting the minimal number of guessing points a string w has to pass through on its way to an accepting state. NFA's with more nondeterminism can achieve greater savings in the number of states over their deterministic counterparts than NFA's with less nondeterminism. On the other hand, for some nontrivial infinite regular languages a deterministic finite automaton (DFA) can already be quite succinct in the sense that NFA's need as many states (and even context-free grammars need as many nonterminals) as the minimal DFA has states.This research was supported in part by the National Science Foundation under Grant No. MCS 76-10076     

Disease Recurrence during Adjuvant Immune Checkpoint Inhibitor Treatment in Metastatic Melanoma: Clinical,Laboratory, and Radiological Characteristics in Patients from a Single Tertiary Referral Center

Despite the dramatic improvements in recurrence-free survival in patients with metastatic melanoma treated with immune checkpoint inhibitors (ICI), a number of patients develop metastases during adjuvant therapy. It is not currently possible to predict which patients are most likely to develop disease recurrence due to a lack of reliable biomarkers. Thus, we retrospectively analyzed the case records of all patients who commenced adjuvant ICI therapy between January 2018 and December 2021 in a single university skin cancer center (n = 46) (i) to determine the rates of disease recurrence, (ii) to examine the utility of established markers, and (iii) to examine whether re-challenge with immunotherapy resulted in clinical response. Twelve out of forty-six (26%) patients developed a relapse on adjuvant immunotherapy in our cohort, and the median time to relapse was 139 days. Adjuvant immunotherapy was continued in three patients. Of the twelve patients who developed recurrence during adjuvant immunotherapy, seven had further disease recurrence within the observation period, with a median time of 112 days after the first progress. There was no significant difference comparing early recurrence (<180 days after initiation) on adjuvant immunotherapy to late recurrence (>180 days after initiation) on adjuvant immunotherapy. Classical tumor markers, including serum lactate dehydrogenase (LDH) and S-100, were unreliable for the detection of disease recurrence. Baseline lymphocyte and eosinophil counts and those during immunotherapy were not associated with disease recurrence. Interestingly, patients with NRAS mutations were disproportionately represented (60%) in the patients who developed disease recurrence, suggesting that these patients should be closely monitored during adjuvant therapy.     

On measuring nondeterminism in regular languages

It is well known that allowing nondeterminism in a finite automaton can produce in the most extreme case an exponential savings in the number of states required to recognize a regular language. This paper studies situations intermediate between forbidding nondeterminism and allowing it. The amount of nondeterminism used by a finite automaton is quantified, so that the decrease in the size of the state space that occurs as the amount of nondeterminism that is permitted increases in increments can be studied. These intermediate situations are shown always to lie between two extremes:(1) there are no savings as the amount of nondeterminism increases incrementally, so that savings occur only when the amount of nondeterminism becomes unlimited;(2) each increment of nondeterminism results in additional savings, the number s of states decreasing approximately as s^1/i, until exponential savings have been achieved after about i = logs/log log s increments.