Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636). PATIENTS AND METHODS: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability. RESULTS: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths. CONCLUSIONS: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.

Altering genotype and phenotype by DNA-mediated gene transfer.

Transformation, or DNA-mediated gene transfer, permits the introduction of new genetic information into a cell and frequently results in a change in phenotype. The transforming DNA is ultimately integrated into a recipient cell chromosome. No unique chromosomal locations are apparent, different lines contain the transforming DNA on different chromosomes. Expression of transformed genes frequently results in the synthesis of new polypeptide products which restore appropriate mutant cells to the wild-type phenotype. Thus transformation provides an in vivo assay for the functional role of DNA sequence organization about specific genes. Transforming genes coding for selectable functions, such as adenine phosphoribosyltransferase or thymidine kinase, have now been isolated by utilizing transformation in concert with molecular cloning. Finally, transformation may provide a general approach to the analysis of complex heritable phenotypes by permitting the distinction between phenotypic changes without concomitant changes in DNA and functional genetic rearrangements.

Effects of mutations in Pr160gag-pol upon tRNA(Lys3) and Pr160gag-plo incorporation into HIV-1.

During HIV-1 viral assembly, both Pr160gag-pol and primer tRNA(Lys3) are packaged into the virus. tRNA(Lys) packaging (both tRNA(Lys3) and tRNA(Lys1,2) is dependent upon the presence of RT sequences within Pr160gag-pol. In this work, we have monitored the effect of Pr160gag-pol mutations upon incorporation of tRNA(Lys3) and Pr160gag-pol into HIV-1 produced from COS-7 cells transfected with mutant HIV-1 proviral DNAs. Mutations include carboxy deletions of Pr160gag-pol and small amino acid insertions and replacements within the various functional domains of the reverse transcriptase (RT). tRNA(Lys3) incorporation was monitored both by 2D PAGE of viral RNA, and by hybridization with tRNA(Lys3)-specific DNA probes. Our data indicates: (1) deletion of integrase sequence has a moderate effect upon select tRNA(Lys3) packaging, while carboxy terminal deletions extending further into the RNase H and connection domains more strongly reduce viral tRNA(Lys3) content; (2) tRNA(Lys3) incorporation is strongly reduced by small inframe amino acid insertions or replacements in the carboxy region of the thumb domain and the amino half of the connection domain of RT, but tRNA(Lys3) incorporation is altered little, or not at all, by similar amino acid insertional mutations within other RT domains, such as the fingers, palm, RNase H, the amino portion of the thumb, and the carboxy region of the connection domain. The inability of connection domain mutant virus to incorporate tRNA(Lys3) and to properly process precursor proteins in the virus is due to the inability of mutant Pr160gag-pol to be incorporated into the virus. These mutant precursor proteins are maintained at levels in the cytoplasm similar to wild-type.

The controversy on the early history of Chagas disease.

Recently historians of medicine have proposed three distinctive accounts of early history of Chagas disease (American trypasonomiasis). According to the first the disease, described by the Brazilian researcher Carlos Chagas in 1909, was "deconstructed" in the 1920s and disappeared for about twenty years, then was recovered in the 1940s, mainly through the epidemiological studies of Emmanuel Dias and his colleagues in Minas Gerais (Brazil). According to the second Chagas disease could not be "deconstructed" in the 1920s because it did not exist at that time. Chagas observations were inaccurate and unreliable and did not define a new human pathology. The entity called today "Chagas disease" appeared in the 1930, principally as the result of investigations of Cecilio Romaña in Argentina. Finally, a third view assumes that "Chagas disease" was constructed gradually between 1909 and the 1950s through the collective efforts of numerous Latino-American researchers. This paper juxtaposes different histories of Chagas disease, and argues that their divergences stems from allegiance to distinct, partly incommensurable epistemological "thought styles". The co-existence of divergent styles of historical investigation, this text proposes, should be perceived as potential source of enrichment of our understanding of the past.

A single amino acid substitution in a common African allele of the CD4 molecule ablates binding of the monoclonal antibody, OKT4.

The CD4 molecule is a relatively non-polymorphic 55 kDa glycoprotein expressed on a subset of T lymphocytes. A common African allele of CD4 has been identified by non-reactivity with the monoclonal antibody, OKT4. The genetic basis for the OKT4- polymorphism of CD4 is unknown. In the present paper, the structure of the CD4 molecule from an homozygous CD4OKT4- individual was characterized at the molecular level. The size of the CD4OKT4- protein and mRNA were indistinguishable from those of the OKT4+ allele. The polymerase chain reaction (PCR) was used to map the structure of CD4OKT4- cDNAs by amplifying overlapping DNA segments and to obtain partial nucleotide sequence after asymmetric amplification. PCR was then used to clone CD4OKT4- cDNAs spanning the coding region of the entire, mature CD4 protein by amplification of two overlapping segments followed by PCR recombination. The nucleotide sequence of CD4OKT4- cDNA clones revealed a G----A transition at bp 867 encoding an arginine----tryptophan substitution at amino acid 240 relative to CD4OKT4+. Expression of a CD4OKT4- cDNA containing only this transition, confirmed that the arginine----tryptophan substitution at amino acid 240 ablates the binding of the mAb OKT4. A positively charged amino acid residue at this position is found in chimpanzee, rhesus macaque, mouse and rat CD4 suggesting that this mutation may confer unique functional properties to the CD4OKT4- protein.

In vivo activation of murine peritoneal macrophages by Nocardia water soluble mitogen (NWSM).

In vitro NWSM has been shown to be a B cell mitogen and a polyclonal activator. Although NWSM has been also shown to be adjuvant active in vivo, motogenicity and polyclonal activation are not observed when this fraction has been administered to mice. In contrast, the experiments reported here demonstrate that after in vivo administration several effects of NWSM on mouse peritoneal macrophages can be observed: NWSM was able to induce an important increase in the ability of peritoneal macrophages to inhibit in vitro growth of tumor cells, to increase their phagocytic activity and to enhance their ability to induce an immune response, following the incubation with an antigen NWSM was able to stimulate phagocytic activity of macrophages of C3H/He Orl. mice (LPS-resistant strain). Those findings suggest that the adjuvant activity of NWSM in vivo can be related to its capacity to activate macrophages.

[Paul-Louis Simond and yellow fever]. / Paul-Louis Simond et la fièvre jaune.

P.L. Simond participated in the Pasteur Institute mission sent to Rio de Janeiro from 1901 to 1905 to investigate yellow fever and was to make an important contribution to the knowledge of the disease. At that time, the aetiologic agent of yellow fever was still unknown, and its transmission by mosquitoes was controversial. Several authors had observed apparent differences in the susceptibility to the illness between African and European populations. Otherwise, the soundness of epidemic control measures then being administered was often called into question. As such, many points needed to be definitely clarified. During the four years they spent in Brazil, the Pasteur Institute scientists--and particularly Simond--achieved important results. They confirmed the viral aetiology of yellow fever, were able to define several pathological aspects of the disease and conduct various serotherapeutic tests. The role of Aedes aegypti (known at the time as Stegomyia fasciata) was also confirmed and the bionomics of the mosquito began to be studied. This research laid the ground for classical measures of controlling the vector and preventing outbreaks of the disease. Furthermore, Marchoux and Simond observed the vertical transmission of yellow fever virus in Ae. aegypti; this phenomenon of major epidemiological importance remained controversial until it was confirmed in the field as recently as 1997. The French scientists were also able to specify many aspects of the epidemiology of yellow fever, particularly its apparent low pathogenicity in young children--a possible explanation for the fact that local residents of endemic zones often had a certain level of immunity as a result of benign infection contracted in childhood. P.L. Simond later spent several months in Martinique where he set up a successful yellow fever vector control programme. Clearly Simond, who had already acquired much expertise in the epidemiology of vector-borne diseases, played a key role in the success of the mission sent by Institute Pasteur to Brazil, and, more generally, in the scientific advances of yellow fever prevention.

[Metaphors of immunology: war and peace]. / Les métaphores de l'immunologie: guerre et paix.

Immunology has always relied on metaphorical language. In its early beginnings, it varied between bellicose images and images that stressed the interaction of immunity mechanisms with the organism's physiological functions overall. In the late nineteenth century, white blood globules were not only compared to 'border police' assigned to rebuffing intruders -- an army formed to combat the invaders -- but were also described as a physiological mechanism for eliminating aged, dead cells, at times exterminators of foreign bodies. Antibodies were described as very powerful, deadly weapons but also as an integral part of mechanisms that allowed cells to assimilate food. This duality of images holds true today. The article analyzes the emergence and development of these images, relating them to the redefinition of immunology as a science of the self and non-self and dissecting them in light of recent events, such as the Aids epidemic.

[Representing and intervening in public health: viruses, mosquitoes and Rockefeller Foundation experts in Brazil]. / Representação e intervenção em saúde pública: vírus, mosquitos e especialistas da Fundação Rockefeller no Brazil.

The attempts by experts from the of the Rockefeller Foundation (RF) to eliminate yellow fever in Brazil were hampered by the pathology's low visibility. Most cases of yellow fever were atypical and easily confused with other fevers. In the 1920s, the RF experts who tried to assess the presence of yellow fever relied mainly on clinical observations. In the 1930s, however, they devised indirect methods of visualizing the presence of the disease agent. Visceroctomy revealed the presence of acute cases of the disease. Mouse protection tests revealed past contacts with the agent. Taken together, these tests enabled the RF specialists to construct maps which indicated zones where the disease was endemic and to target specific anti-yellow fever campaigns based on selective elimination of the yellow fever vector, that is, the mosquito Aedes aegypti. In public health, like in the sciences, representation practices shape intervention.

[Ludwik Fleck and the history of sciences today]. / Ludwik Fleck e a presente história das ciências.

In the 1920's and 30's the physician and epistemologist Ludwik Fleck developed a highly original ideas on science. These ideas were rooted in Fleck's own experience as bacteriologist and immunologist and, on the other hand, in the practice-based thought of the Polish School of Philosophy of Medicine. Fleck affirmed that 'scientific facts' are constructed by groups of scientists, in his terms, by "thought collectives". Each thought collective elaborates a "thought style" which contains norms, concepts and practices of that collective. Newcomers to a professional community are socialized into its specific thought style and develop an unique way of viewing the world. Scientific facts produced by a given thought collective are therefore shaped by that collective's thought style, and are incommensurable with facts produced by other thought collectives. The incommensurability of scientific facts and its consequence, the need to 'translate' these facts into the style of different thought collectives in an inter-community use are, Fleck proposed, an important source of innovations in science and in society. Fleck ideas were rediscovered in the 1960's and 70's, first by Thomas Kuhn, who in the introduction to his book, The structure of scientific revolutions, acknowledges his ties with Fleck's thought, then by sociologists of science. Beyond their direct influence, Fleck's epistemology has many affinities with new trends in science studies, focused on the scientists' practices, and interested in their material, discursive and social techniques.

Ludwik Fleck on the social construction of medical knowledge.

The subject of the development and transmission of medical knowledge has remained, until recently, relatively little studied by medical sociologists. But as early as the 1930s the pioneering studies of Ludwick Fleck, a physician and historian of science, dealt with the evolution of medical knowledge and the genesis of medical facts. Starting with a reflection on his own experience as clinical bacteriologist and immunologist, Fleck developed highly original views on subjects such as the influence of patterns of specialization of physicians on the medical knowledge they produced, the impact of popular models of disease on expert ones, and the importance of the circulation of ideas between distinct, and--according to Fleck--incommensurable 'thought collectives' (medical scientists, general practitioners and patients) for the development of innovations in medicine. The aim of this article is to analyze Fleck's vision of medicine and to select among his ideas those which may be of interest for sociologists of medicine today.

[Scientific facts and their public: the history of the diagnosis of syphilis]. / Les "faits scientifiques" et leur public: l'histoire de la détection de la syphilis.

In the 1910's and 1920', thanks to the conjunction of scientific views concerning the specificity of anti-bacterial antibodies, of lay ideas about the existence of anti-bacterial antibodies and of the perceived importance of developing a syphilis test for public health officials, the community of serologists collectively transformed a relatively inefficient diagnostic test described by Wassermann in 1906 into an "incontestable scientific fact". This "scientific fact" established the equivalence: Wassermann positive individual=person infected with the germ Treponema pallidum, the etiological agent of syphilis. It modified the boundaries of the nosologic entity "syphilis", medical practices, professional attitudes, lay perceptions of syphilis, and health policies. In the 1950's, however, discrepancies between Wassermann test data and epidemiological data and, on the other hand, the development of specific anti-treponemal tests, destabilized the previously stabilized "scientific fact". A high percentage of Wassermann positive individuals were redefined as "biological false positifs", that is persons who suffered from chronic affections able to induce positive results of the Wassermann test. The equivalence Wassermann positive person=individual infected by Treponema pallidum was replaced by the equation: Wassermann positive person=individual infected by Treponema pallidum or biological false positive. The new perception of the Wassermann test again changed scientific views, professional practices and lay beliefs. The history of the Wassermann reaction illustrates the complicated interaction between "scientific facts" and "social facts", and the mutual shaping of both.