Sweet Immune Checkpoint Targets to Enhance T Cell Therapy.

Despite tremendous success against hematological malignancies, the performance of chimeric Ag receptor T cells against solid tumors remains poor. In such settings, the lack of success of this groundbreaking immunotherapy is in part mediated by ligand engagement of immune checkpoint molecules on the surface of T cells in the tumor microenvironment. Although CTLA-4 and programmed death-1 (PD-1) are well-established checkpoints that inhibit T cell activity, the engagement of glycans and glycan-binding proteins are a growing area of interest due to their immunomodulatory effects. This review discusses exemplary strategies to neutralize checkpoint molecules through an in-depth overview of genetic engineering approaches aimed at overcoming the inhibitory programmed death ligand-1 (PD-L1)/PD-1 axis in T cell therapies and summarizes current knowledge on glycoimmune interactions that mediate T cell immunosuppression.

Synthesis of Oligonucleotides containing the cis-Interstrand Crosslink Produced by Mitomycins in their Reaction with DNA.

Mitomycin C (MC) an antitumor drug and decarbamoylmitomycin C (DMC), a derivative of MC lacking the carbamoyl moiety, are DNA alkylating agents which can form DNA interstrand crosslinks (ICLs) between deoxyguanosine residues located on opposing DNA strands. MC forms primarily deoxyguanosine adducts with a 1"-R stereochemistry at the guanine-mitosene bond (1"-α, trans) whereas DMC forms mainly adducts with a 1"-S stereochemistry (1"-ß, cis). The crosslinking reaction is diastereospecific: trans-crosslinks are formed exclusively at CpG sequences, while cis-crosslinks are formed only at GpC sequences. Until now, oligonucleotides containing 1"-ß-deoxyguanosine adducts or ICL at a specific site could not be synthesized, thus limiting the investigation of the role played by the stereochemical configuration at C1'' in the toxicity of these compounds. Here, a novel biomimetic synthesis to access these substrates is presented. Structural proof of the adducted oligonucleotides and ICL were provided by enzymatic digestion to nucleosides, high resolution mass spectral analysis, CD spectroscopy and UV melting temperature studies. Finally, a virtual model of the 25-mer 1"-ß ICL synthesized was created to explore the conformational space and structural features of the crosslinked duplex.

Sequence-Dependent Diastereospecific and Diastereodivergent Crosslinking of DNA by Decarbamoylmitomycin C.

Mitomycin C (MC), a potent antitumor drug, and decarbamoylmitomycin C (DMC), a derivative lacking the carbamoyl group, form highly cytotoxic DNA interstrand crosslinks. The major interstrand crosslink formed by DMC is the C1'' epimer of the major crosslink formed by MC. The molecular basis for the stereochemical configuration exhibited by DMC was investigated using biomimetic synthesis. The formation of DNA-DNA crosslinks by DMC is diastereospecific and diastereodivergent: Only the 1''S-diastereomer of the initially formed monoadduct can form crosslinks at GpC sequences, and only the 1''R-diastereomer of the monoadduct can form crosslinks at CpG sequences. We also show that CpG and GpC sequences react with divergent diastereoselectivity in the first alkylation step: 1"S stereochemistry is favored at GpC sequences and 1''R stereochemistry is favored at CpG sequences. Therefore, the first alkylation step results, at each sequence, in the selective formation of the diastereomer able to generate an interstrand DNA-DNA crosslink after the "second arm" alkylation. Examination of the known DNA adduct pattern obtained after treatment of cancer cell cultures with DMC indicates that the GpC sequence is the major target for the formation of DNA-DNA crosslinks in vivo by this drug.

Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin†C.

Mitomycin C (MC), an antitumor drug, and decarbamoylmitomycin C (DMC), a derivative of MC, alkylate DNA and form deoxyguanosine monoadducts and interstrand crosslinks (ICLs). Interestingly, in mammalian culture cells, MC forms primarily deoxyguanosine adducts with a 1"-R stereochemistry at the guanine-mitosene bond (1"-α) whereas DMC forms mainly adducts with a 1"-S stereochemistry (1"-ß). The molecular basis for the stereochemical configuration exhibited by DMC has been investigated using biomimetic synthesis. Here, we present the results of our studies on the monoalkylation of DNA by DMC. We show that the formation of 1"-ß-deoxyguanosine adducts requires bifunctional reductive activation of DMC, and that monofunctional activation only produces 1"-α-adducts. The stereochemistry of the deoxyguanosine adducts formed is also dependent on the regioselectivity of DNA alkylation and on the overall DNA CG content. Additionally, we found that temperature plays a determinant role in the regioselectivity of duplex DNA alkylation by mitomycins: At 0 °C, both deoxyadenosine (dA) and deoxyguanosine (dG) alkylation occur whereas at 37 °C, mitomycins alkylate dG preferentially. The new reaction protocols developed in our laboratory to investigate DMC-DNA alkylation raise the possibility that oligonucleotides containing DMC 1"-ß-deoxyguanosine adducts at a specific site may be synthesized by a biomimetic approach.

Isolation and Rationale for the Formation of Isomeric Decarbamoylmitomycin C- N6-deoxyadenosine Adducts in DNA.

Mitomycin C (MC) is an anticancer agent that alkylates DNA to form monoadducts and interstrand cross-links. Decarbamoylmitomycin C (DMC) is an analogue of MC lacking the carbamate on C10. The major DNA adducts isolated from treatment of culture cells with MC and DMC are N2-deoxyguanosine (dG) adducts and adopt an opposite stereochemical configuration at the dG-mitosene bond. To elucidate the molecular mechanisms of DMC-DNA alkylation, we have reacted short oligonucleotides, calf thymus, and M. luteus DNA with DMC using biomimetic conditions. These experiments revealed that DMC is able to form two stereoisomeric deoxyadenosine (dA) adducts with DNA under bifuntional reduction conditions and at low temperature. The dA-DMC adducts formed were detected and quantified by HPLC analysis after enzymatic digestion of the alkylated DNA substrates. Results revealed the following rules for DMC dA alkylation: (i) DMC dA adducts are formed at a 48- to 4-fold lower frequency than dG adducts, (ii) the 5'-phosphodiester linkage of the dA adducts is resistant to snake venom diesterase, (iii) end-chain dA residues are more reactive than internal ones in duplex DNA, and (iv) nucleophilic addition by dA occurs on both faces of DMC and the ratio of stereoisomeric dA adducts formed is dependent on the end bases located at the 3' or 5' position. A key finding was to discover that temperature plays a determinant role in the regioselectivity of duplex DNA alkylation by DMC: at 0 °C, both dA and dG alkylation occur, whereas at 37 °C, DMC preferentially alkylates dG residues.

Acetone promoted 1,4-migration of an alkoxycarbonyl group on a syn-1,2-diamine.

A 2-protected cis-amino mitosene undergoes an irreversible acetone promoted isomerization and converts to the 1-isomer. Kinetic studies and DFT calculations of the reaction are reported. An organocatalytic mechanism is proposed, involving a covalent intermediate formed by reaction of the mitosene and acetone.

Multimodal management of giant solid hemangioblastomas in two patients with preoperative embolization.

Background: Hemangioblastomas are benign vascular neoplasms, World Health Organization grade I, with the most frequent location in the cerebellum. Complete microsurgical resection can be a challenge due to excessive bleeding, which is why preoperative embolization takes importance. Case Description: Two clinical cases are presented, a 25-year-old woman and a 75-year-old man, who presented with intracranial hypertension symptoms due to obstructive hydrocephalus; a ventriculoperitoneal shunt was placed in both cases; in addition, they presented with cerebellar signs. Both underwent embolization with ethylene vinyl alcohol copolymer, with blood flow reduction. After that, they underwent microsurgical resection within the 1st-week post embolization, obtaining, in both cases, gross total resection without hemodynamic complications, with clinical improvement and good surgical outcome. It is worth mentioning that surgical management is the gold standard that allows a suitable surgical approach, like in our patients, for which a lateral suboccipital craniotomy was performed. Conclusion: Solid hemangioblastomas are less frequent than their cystic counterparts. The treatment is the surgical resection, which is a challenge and always has to be considered as an arteriovenous malformation in the surgical planning, including preoperative embolization to reduce perioperative morbidity and mortality and get good outcomes.

Transclival endoscopic approach for prepontine cistern neurocysticercosis causing trigeminal neuralgia: illustrative case.

BACKGROUND: Neurocysticercosis (NCC) is a public health problem in most of the world. Approximately 50 million people worldwide experience this disease, and it remains one of the most important causes of neurological morbidity. Extraparenchymal NCC (basal cisterns) is associated with high rates of morbidity and mortality. Currently, minimally invasive approaches, including the endoscopic endonasal approach, are used with good functional results. OBSERVATIONS: A 25-year-old patient presented with headache and pain in the left hemiface. Magnetic resonance imaging (MRI) showed cystic lesions in the prepontine basal cisterns compressing and displacing the left trigeminal nerve. The cysticercal lesions were excised using a transclival endoscopic approach. There were no complications during surgery, and pathology confirmed the diagnosis of NCC. The pain subsided after surgery. No residual cysts were observed on control MRI. LESSONS: Minimally invasive approaches can be used to treat tumor and infectious problems of the skull base, as in this case, with good functional results. https://thejns.org/doi/10.3171/CASE24223.

Trigeminal neuralgia secondary to vascular compression and neurocysticercosis: illustrative case.

BACKGROUND: Trigeminal neuralgia (TN) is a frequent neurosurgical problem negatively influencing the quality of life of patients. The standard surgical treatment is microvascular decompression for primary cases and decompression of the mass effect, mainly tumors, for secondary cases. Neurocysticercosis (NCC) in the cerebellopontine angle is a rare etiology of TN. The authors report a case in which NCC cysts around the trigeminal nerve coexisted with a vascular loop, which compressed the exit of the trigeminal nerve from the pons. OBSERVATIONS: A 78-year-old woman presented with a 3-year history of persistent severe pain in the left side of her face, refractory to medical treatment. On gadolinium-enhanced magnetic resonance imaging, cystic lesions were observed around the left trigeminal nerve and a vascular loop was also present and in contact with the nerve. A retrosigmoid approach for cyst excision plus microvascular decompression of the trigeminal nerve was successfully performed. There were no complications. The patient was discharged without facial pain. LESSONS: Albeit rare, TN secondary to NCC cysts should be considered in the differential diagnosis in NCC-endemic regions. In this case, the cause of the neuralgia was probably both problems, because when both were treated, the patient improved.

Transventricular endoscopic approach to the anterior interhemispheric fissure for neurocysticercosis: illustrative cases.

BACKGROUND: Neurocysticercosis (NCC) is a global public health problem. It is a complex disease to manage and a cause of great morbidity and mortality in affected patients. Conventional surgical approaches have been used for many years, but currently, minimally invasive approaches are being used with good results. The authors present a case of NCC in the anterior interhemispheric fissure that was treated with a transventricular endoscopic approach. OBSERVATIONS: A 32-year-old male patient was admitted for persistent moderate headache and dizziness. Gadolinium-enhanced magnetic resonance imaging (MRI) showed multiple parenchymal, ventricular, and subarachnoid cystic lesions, especially in the anterior interhemispheric space. A transventricular endoscopic approach was selected and applied. There were no complications during surgery. Pathological analysis confirmed the diagnosis of NCC. Control MRI demonstrated the absence of cysts in the anterior interhemispheric space. LESSONS: Minimally invasive approaches are an excellent alternative for patients with NCC, especially if a patient requires more than one surgery.